TY - JOUR A1 - Sterzing, Florian A1 - Engenhart-Cabillic, Rita A1 - Flentje, Michael A1 - Debus, Jürgen T1 - Image-Guided Radiotherapy : A New Dimension in Radiation Oncology JF - Deutsches Ärzteblatt International N2 - Background: The vital importance of imaging techniques in radiation oncology now extends beyond diagnostic evaluation and treatment planning. Recent technical advances have enabled the integration of various imaging modalities into the everyday practice of radiotherapy directly at the linear accelerator, improving the management of inter-and intrafractional variations. Methods: We present the topic of image-guided radiotherapy (IGRT) on the basis of a selective review of the literature. Results: IGRT can be performed with the aid of ultrasound, 2D X-ray devices, and computed tomography. It enables instant correction for positioning deviations and thereby improves the precision of daily radiotherapy fractions. It also enables immediate adjustment for changes in the position and filling status of the internal organs. Anatomical changes that take place over the course of radiotherapy, such as weight loss, tumor shrinkage, and the opening of atelectases, can be detected as they occur and accounted for in dosimetric calculations. There have not yet been any randomized controlled trials showing that IGRT causes fewer adverse effects or improves tumor control compared to conventional radiotherapy. Conclusion: IGRT is more precise and thus potentially safer than conventional radiotherapy. It also enables the application of special radiotherapeutic techniques with narrow safety margins in the vicinity of radiosensitive organs. Proper patient selection for IGRT must take account of the goals of treatment and the planning characteristics, as well as the available technical and human resources. IGRT should be used for steep dose gradients near organs at risk, for highly conformal dose distributions in the gastrointestinal tract where adjustment for filling variations is needed, for high-precision dose escalation to avoid geographic miss, and for patients who cannot lie perfectly still because of pain or claustrophobia. KW - cone-beam ct KW - megavoltage computed-tomography KW - prostate-cancer KW - helical tomotherapy KW - guidance KW - therapy KW - limitations KW - head Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140771 VL - 108 IS - 16 ER - TY - THES A1 - Beykan, Seval T1 - Implementation and Optimization of Dosimetry for Theranostics in Radiopeptide Therapies T1 - Implementierung und Optimierung der Dosimetrie für die Theranostik in Radiopeptidtherapien N2 - Peptide receptor radionuclide therapy (PRRT) is a molecular targeted radiation therapy involving the systemic administration of radiolabeled somatostatin receptor binding peptides designed to target with high affinity and specificity receptors overexpressed on tumors. Peptides are applied which either target as agonist (with internalization) or antagonist (little to no internalization). Recently, two novel antagonistic agents have been developed for clinical use: OPS202 and OPS201. 68Ga-labelled OPS202 is used for diagnostic purposes with positron emission tomography and 177Lu-labelled OPS201 is used for the therapy in patients with neuroendocrine tumors (NETs). Both agents are presently under clinical evaluation. Despite the very low internalization rate, the use of somatostatin receptor antagonists which target more binding sites on receptors are expected to result in higher specificity, more favorable pharmacokinetics and higher tumor retention and better visualization than the agonists. The main goal of this thesis was analyzing the biodistribution, biokinetics and internal dosimetry of the recently developed somatostatin receptor antagonists (OPS201 and OPS202) for therapeutic and diagnostic purposes in different species (mice, pigs and patients). In addition, an analysis of the influence of image quantification and the integration of time activity curves on kidney dosimetry in a pig model was carried out. Furthermore, extrapolation methods, which are used for predicting organ absorbed doses for humans based on preclinical animal models, were systematically compared for blood, liver, and kidneys of OPS201 injected species. Based on the OPS202 injected patients’ investigations, 68Ga-OPS202 shows promising biodistribution and imaging properties with tumor contrast which is optimal one hour after injection of the radiotracer. OPS202 is well tolerated and delivers absorbed doses to organs that are lower than those by 18F-FDG and similar to other 68Ga-labeled somatostatin receptor ligands. As a result of 68Ga OPS202 injection, the highest absorbed doses were observed in the urinary bladder (0.10 mGy/MBq) and kidneys (0.84 mGy/MBq). The calculated mean effective dose coefficient of 68Ga-OPS202 injected patients was 0.024 mSv/MBq (3.6 mSv for 150 MBq 68Ga-OPS202 injection) which is similar to other 68Ga-labeled compounds. Based on the OPS201 biokinetics and dosimetry investigations, after the injection of 177Lu-OPS201, a fast blood clearance of the compound is observed in the first phase (half-life: 1.83 h) for each species. 10 min after injection, less than 5% of the injected activity per milliliter of blood circulates in pigs and humans. The analysis of the mice, pig and preliminary patient data provides evidence that, patients enrolled in a phase 1 177Lu-OPS201 trial would not be at risk of overexposure. Based on our results, for 177Lu labelled studies, late time points after 72 h have a great impact on absorbed dose calculations. That is why follow-up times especially at late time points (more than 72 h) are required for the time-integrated activity coefficient (TIAC) calculations in order to represent the area under the curve appropriately and to analyze both biokinetics and dosimetry accurately. In addition, to find the most adequate extrapolation methods that minimize the interspecies differences of dosimetry data, several extrapolation methods from animal to human have been tested. For OPS201 time scaling or combination of relative mass and time scaling results in most similar TIAC values, if the organ mass ratios between the species are high. In time scaling, the scan/sampling time is scaled by using the ratio of the whole body masses of the respective species. In relative mass scaling, the TIACs are scaled based on the ratio of the whole body and organ mass of respective species. Other methods tested showed higher deviations. For the study on the influence of image quantification and the choice of the optimal scanning time points, a study in a pig model, which was performed in collaboration with Aalborg University and Octreopharm Sciences GmbH, was reanalyzed. As kidneys are organs-at-risk in PRRT with 177Lu labelled peptides, several quantification methods, based on 2D and 3D quantitative imaging were chosen. For this purpose, a 3D printed pig kidney phantom was prepared and measured with/without background activities representing the activities in the pig SPECT/CT scans. The phantom dosimetry data based on multiple SPECT/CT images and based on multiple planar images in combination with one SPECT/CT scan (MP1S Imaging) were compared to the pig dosimetry. The calculated TIACs of the phantom with background based on multiple SPECT/CT and MP1S imaging were quite similar to the multiple SPECT/CT based pig TIAC. In addition, in order to investigate the effect of late time points on dosimetry and absorbed dose values in 177Lu therapies, the difference, associated with eliminating the late two scan time points, on the TIACs was analyzed. When the TIACs (including all time points) of the pig based on multiple SPECT/CT and MP1S imaging were investigated, the use of MP1S imaging results in considerably lower TIAC values to the kidney (by a factor of 1.4). With eliminating late time points from the created time activity curve, the factor increases up to 2.4 times with a corresponding increase in TIAC uncertainties. As a consequence, further evaluation of 68Ga-OPS202 for PET/CT imaging and 177Lu-OPS201 for the treatments of NET patients is necessary. In particular, a head-to-head comparison of agonists and OPS peptides with respect to biokinetics, biodistribution and dosimetry would be helpful. In addition, the influence of the late scan time points on dosimetry needs further attention in particular for kidney dosimetry N2 - Die Peptidrezeptor-Radionuklidtherapie (PRRT) beinhaltet die systemische Verabreichung von radioaktiv markierten Somatostatinrezeptor-bindende Peptiden. Sie zielt darauf ab, Rezeptoren, die in Tumoren überexprimiert sind, mit hoher Affinität und Spezifität anzusprechen. Es werden Peptide eingesetzt, die entweder als Agonist (mit Internalisierung) oder Antagonist (wenig bis gar keine Internalisierung) wirken. Vor kurzem wurden zwei neue antagonistische Wirkstoffe für den klinischen Einsatz entwickelt: OPS202 und OPS201. 68Ga markiertes OPS202 wird für diagnostische Zwecke mit der Positronen-Emissions-Tomographie und 177Lu markiertes OPS201 für die Therapie von Patienten mit neuroendokrinen Tumoren (NETs) verwendet. Beide Wirkstoffe befinden sich derzeit in der klinischen Erprobung. Trotz der sehr niedrigen Internalisierungsrate wird erwartet, dass der Einsatz von Somatostatinrezeptor-Antagonisten, die mehr Bindungsstellen an Rezeptoren ansprechen, zu einer höheren Spezifität, einer günstigeren Pharmakokinetik und einer höheren Tumorretention und besseren Visualisierung als die Agonisten führt. Das Hauptziel dieser Arbeit war die Analyse der Biodistribution, Biokinetik und der internen Dosimetrie der neu entwickelten Somatostatinrezeptor-Antagonisten (OPS201 und OPS202) für therapeutische und diagnostische Zwecke in verschiedenen Spezies (Mäuse, Schweine und Patienten). Darüber hinaus wurde eine Analyse des Einflusses der Bildquantifizierung und der Integration von Zeitaktivitätskurven auf die Nierendosimetrie in einem Schweinemodell durchgeführt. Zudem wurden Extrapolationsmethoden, die zur Vorhersage der Energiedosen für das Blut, die Leber und die Nieren für den Menschen auf der Grundlage präklinischer Tiermodelle, die mit OPS201 injiziert wurden, systematisch verglichen. Basierend auf den Patientenuntersuchungen mit OPS202 zeigt 68Ga-OPS202 vielversprechende Biodistributions- und Abbildungseigenschaften mit einem Tumorkontrast, der eine Stunde nach Injektion des Radiotracers optimal ist. OPS202 ist gut verträglich; die Energiedosen in den Organen sind niedriger als die von 18F-FDG und ähnlich wie andere 68Ga-markierte Somatostatinrezeptorliganden. Nach einer Injektion von OPS202, das mit 68Ga markiert wurde, wurden die höchsten Energiedosen in der Harnblase (0.10 mGy/MBq) und den Nieren (0.84 mGy/MBq) beobachtet. Der berechnete mittlere effektive Dosiskoeffizienten von Patienten, die mit 68Ga-OPS202 injiziert wurden, betrug 0.024 mSv/MBq (3.6 mSv für 150 MBq 68Ga-OPS202), ähnlich wie bei anderen 68Ga-markierten Verbindungen. Basierend auf den biokinetischen und dosimetrischen Untersuchungen von OPS201 wird nach der Injektion von 177Lu-OPS201 in der ersten Phase (Halbwertszeit: 1.83 h) für jede Spezies eine schnelle Ausscheidung der Verbindung beobachtet. 10 Minuten nach der Injektion zirkulieren weniger als 5% der injizierten Aktivität pro Milliliter Blut bei Schweinen und Menschen. Die Analyse der Daten von Mäusen, Schweinen und vorläufigen Patienten liefert Hinweise darauf, dass Patienten, die in eine 177Lu-OPS201-Studie aufgenommen werden, nicht dem Risiko für eine Überexposition ausgesetzt wären. Basierend auf unseren Ergebnissen werden für 177Lu markierte Studien Nachbeobachtungszeiten insbesondere zu späten Zeitpunkten (mehr als 72 h) für die Berechnungen des zeitintegrierten Aktivitätskoeffizienten (TIAC) benötigt, um die Fläche unter der Kurve angemessen darzustellen und sowohl die Biokinetik als auch die Dosimetrie genau zu analysieren. Späte Zeitpunkte (nach 72 h) haben einen großen Einfluss auf die Berechnung der Energiedosis. Darüber hinaus wurden mehrere Extrapolationsmethoden vom Tier auf den Menschen getestet, um die geeignetsten Extrapolationsmethoden zu finden, die die Unterschiede zwischen den verschiedenen Spezies von Dosimetrie-Daten minimieren. Für OPS201 ergibt die Zeitskalierung oder die Kombination von relativer Masse und Zeitskalierung die ähnlichsten TIAC-Werte, wenn die Organmassenverhältnisse zwischen den Spezies hoch sind. Bei der Zeitskalierung wird die Scan-/Samplingzeit durch das Verhältnis der Ganzkörpermassen der jeweiligen Spezies skaliert. Bei der relativen Massenskalierung werden die TIACs basierend auf dem Verhältnis der Ganzkörper- und Organmasse der jeweiligen Spezies skaliert. Andere getestete Methoden zeigten höhere Abweichungen. Um den Einfluss der Bildquantifizierung und die Wahl der optimalen Scanzeitpunkte zu untersuchen, wurde eine Studie in einem Schweinemodell, die in Zusammenarbeit mit der Universität Aalborg und der Octreopharm Sciences GmbH durchgeführt wurde, neu analysiert. Da die Nieren bei PRRT mit 177Lu markierten Peptiden Risikoorgane sind, wurden mehrere Quantifizierungsmethoden ausgewählt, die auf 2D- und 3D-Bildgebung basieren. Zu diesem Zweck wurde ein 3D gedrucktes Schweine-Nierenphantom vorbereitet und, mit und ohne Hintergrundaktivitäten, die den Aktivitäten in den Schweinescans entsprechen, gemessen und quantifiziert,. Dosimetrie-Daten, die aus dem Schweinescan basierend auf mehreren 3D-Bildern und basierend auf mehreren 2D-Planarbildern in Kombination mit einem SPECT/CT-Bild („MP1S-Imaging“) gewonnen wurden, wurden mit den Ergebnissen der Phantomscans verglichen. Die so ermittelten TIACs des Phantoms mit Hintergrund, basierend auf beiden Bildgebungstechniken, entsprachen in etwa den Ergebnissen derjenigen Schweinedaten, die auf mehrfachen SPECT/CT-Aufnahmen basierten. Um die Auswirkungen der späten Zeitpunkte auf die Dosimetrie und die Werte der Energiedosen in 177Lu Therapien zu untersuchen, wurde außerdem der Unterschied, der mit der Eliminierung der späten zwei Scanzeitpunkte verbunden ist, auf die TIACs analysiert. Wenn auf mehreren SPECT/CT- und Hybrid-Bildern basierten TIACs des Schweins untersucht wurden, war die berechnete TIAC (einschließlich aller Zeitpunkte) basierend auf mehreren SPECT/CT-Bildern im Vergleich zur Hybrid Imaging um den Faktor 1.4 höher. Durch die Eliminierung von späten Zeitpunkten aus der erstellten Zeitaktivitätskurve erhöht sich der TIAC um den Faktor 2.4 mit entsprechend höheren TIAC Unsicherheiten. Daher ist zu folgern, dass eine weitere Evaluierung von 68Ga-OPS202 für die PET/CT-Bildgebung und 177Lu-OPS201 für die Behandlung von NET-Patienten erforderlich ist. Insbesondere wäre ein direkter Vergleich von Agonisten und OPS-Peptiden in Bezug auf Biokinetik, Biodistribution und Dosimetrie hilfreich. Darüber hinaus bedarf der Einfluss der späten Zeitpunkte bei Dosimetrie-Scans weiterer Aufmerksamkeit, insbesondere bei der Nierendosimetrie. KW - biodistribution KW - biokinetics KW - internal dosimetry KW - somatostatin receptor antagonists KW - 177Lu-OPS201 KW - therapy KW - 68Ga-OPS202 KW - diagnostics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199553 ER - TY - JOUR A1 - Hetz, Susan A1 - Acikgoez, Ali A1 - Voss, Ulrike A1 - Nieber, Karen A1 - Holland, Heidrun A1 - Hegewald, Cindy A1 - Till, Holger A1 - Metzger, Roman A1 - Metzger, Marco T1 - In Vivo Transplantation of Neurosphere-Like Bodies Derived from the Human Postnatal and Adult Enteric Nervous System: A Pilot Study JF - PLOS ONE N2 - Recent advances in the in vitro characterization of human adult enteric neural progenitor cells have opened new possibilities for cell-based therapies in gastrointestinal motility disorders. However, whether these cells are able to integrate within an in vivo gut environment is still unclear. In this study, we transplanted neural progenitor-containing neurosphere-like bodies (NLBs) in a mouse model of hypoganglionosis and analyzed cellular integration of NLB-derived cell types and functional improvement. NLBs were propagated from postnatal and adult human gut tissues. Cells were characterized by immunohistochemistry, quantitative PCR and subtelomere fluorescence in situ hybridization (FISH). For in vivo evaluation, the plexus of murine colon was damaged by the application of cationic surfactant benzalkonium chloride which was followed by the transplantation of NLBs in a fibrin matrix. After 4 weeks, grafted human cells were visualized by combined in situ hybridization (Alu) and immunohistochemistry (PGP9.5, GFAP, SMA). In addition, we determined nitric oxide synthase (NOS)-positive neurons and measured hypertrophic effects in the ENS and musculature. Contractility of treated guts was assessed in organ bath after electrical field stimulation. NLBs could be reproducibly generated without any signs of chromosomal alterations using subtelomere FISH. NLB-derived cells integrated within the host tissue and showed expected differentiated phenotypes i.e. enteric neurons, glia and smooth muscle-like cells following in vivo transplantation. Our data suggest biological effects of the transplanted NLB cells on tissue contractility, although robust statistical results could not be obtained due to the small sample size. Further, it is unclear, which of the NLB cell types including neural progenitors have direct restoring effects or, alternatively may act via 'bystander' mechanisms in vivo. Our findings provide further evidence that NLB transplantation can be considered as feasible tool to improve ENS function in a variety of gastrointestinal disorders. KW - Hirschsprung disease KW - benzalkonium chloride KW - progenitors KW - GUT KW - rat KW - colon KW - biology KW - therapy KW - neural stem-cell KW - motility disorders Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116793 VL - 9 IS - 4 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Niemczyk, Gabriele A1 - Rehberg-Weber, Karin A1 - Wernsdörfer, Colin T1 - Interferon Beta-1a (AVONEX®) as a treatment option for untreated patients with multiple sclerosis (AXIOM): a prospective, observational study JF - International Journal of Molecular Sciences N2 - The efficacy and safety of first-line disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in pivotal, randomized trials, but these studies do not reflect the routine care setting where treatment gaps or switches are common. The Avonex as Treatment Option for Untreated MS Patients (AXIOM) trial assessed the efficacy of newly-initiated intramuscular interferon beta-1a (IM IFNb-1a) after a treatment-free interval, with particular consideration of the previous course of disease and therapy. The AXIOM trial was an open, 12-month, observational, non-interventional study with a retrospective and a prospective part conducted in Germany. RRMS patients with a treatment-free interval of at least three months were included and treated with IFNb-1a for up to 12 months. Relapse rate, disability progression, injection-related parameters and quality of life observed during the prospective part were compared with retrospectively-collected data. Two hundred and thirty five RRMS patients participated in AXIOM. The mean relapse rate decreased from 1.1 in the three months before baseline to 0.2 per quarter during the twelve-month observational period; the Multiple Sclerosis Functional Composite score improved during twelve months of IM IFNb-1a treatment, while the Expanded Disability Status Scale score did not change over the course of this study. Compared to previous DMTs (IM IFNb-1a, subcutaneous IFNb-1a (SC IFNb-1a), SC IFNb-1b, glatiramer acetate), the patients experienced less injection site reactions and flu-like symptoms, with a stated improved quality of life. IM IFNb-1a was effective and well accepted in RRMS patients with no or discontinued previous therapy. These results from the routine care setting may inform optimization of DMT treatment in RRMS, but need confirmation in further studies. KW - subcutaneous injection KW - therapy KW - trial KW - relapsing-remitting multiple sclerosis KW - injection site reactions; KW - efficacy KW - quality of life KW - disease-modifying therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148487 VL - 16 ER - TY - JOUR A1 - Krämer, Johannes A1 - Bijnens, Bart A1 - Störk, Stefan A1 - Ritter, Christian O. A1 - Liu, Dan A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Weidemann, Frank T1 - Left ventricular geometry and blood pressure as predictors of adverse progression of Fabry cardiomyopathy JF - PLoS ONE N2 - Background In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated. Methods In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed. Results Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05). Conclusions LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy. KW - cardiovascular magnetic resonance KW - clinical manifestations KW - disease KW - identification KW - fibrosis KW - 2-dimensional speckle tracking KW - myocardial infarction KW - therapy KW - diagnosis KW - impact Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145131 VL - 10 IS - 11 ER - TY - JOUR A1 - Benoit, Sandrine A1 - Goebeler, Matthias T1 - Mepacrine in recalcitrant cutaneous lupus erythematosus: old-fashioned or still useful? JF - Acta Dermato-Venereologica N2 - Treatment of recalcitrant cutaneous lupus erythematosus (CLE) is challenging. In situations where conventional treatment approaches fail mepacrine - an antimalarial/antiinfiammatory drug that has fallen into oblivion in the last decades might still be a promising option. We retrospectively analysed medical records of 10 patients with refractory CLE that were treated with mepacrine (100-200 mg/day) as mono- or combination therapy for various time intervals between 2001 and 2013 at the University Hospital Wurzburg. Mepacrine was generally well tolerated. Side effects were mild and usually resolved after reduction or cessation. Over 50% of the patients experienced amelioration of their symptoms despite a previously recalcitrant clinical course. Altogether, our data demonstrate that mepacrine still remains a useful and effective therapeutic option for otherwise treatment-resistant CLE. KW - classification KW - therapy KW - cutaneous lupus erythematosus KW - quinacrine KW - mepacrine KW - smoking Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149181 VL - 95 ER - TY - JOUR A1 - Kienle-Garrido, Melina-Lorén A1 - Breitenbach, Tim A1 - Chudej, Kurt A1 - Borzì, Alfio T1 - Modeling and numerical solution of a cancer therapy optimal control problem JF - Applied Mathematics N2 - A mathematical optimal-control tumor therapy framework consisting of radio- and anti-angiogenesis control strategies that are included in a tumor growth model is investigated. The governing system, resulting from the combination of two well established models, represents the differential constraint of a non-smooth optimal control problem that aims at reducing the volume of the tumor while keeping the radio- and anti-angiogenesis chemical dosage to a minimum. Existence of optimal solutions is proved and necessary conditions are formulated in terms of the Pontryagin maximum principle. Based on this principle, a so-called sequential quadratic Hamiltonian (SQH) method is discussed and benchmarked with an “interior point optimizer―a mathematical programming language” (IPOPT-AMPL) algorithm. Results of numerical experiments are presented that successfully validate the SQH solution scheme. Further, it is shown how to choose the optimisation weights in order to obtain treatment functions that successfully reduce the tumor volume to zero. KW - cancer KW - therapy KW - optimal control problem Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177152 VL - 9 IS - 8 ER - TY - JOUR A1 - Kessler, Almuth F. A1 - Feldheim, Jonas A1 - Schmitt, Dominik A1 - Feldheim, Julia J. A1 - Monoranu, Camelia M. A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - Monopolar Spindle 1 Kinase (MPS1/TTK) mRNA Expression is Associated with Earlier Development of Clinical Symptoms, Tumor Aggressiveness and Survival of Glioma Patients JF - Biomedicines N2 - Inhibition of the protein kinase MPS1, a mitotic spindle-checkpoint regulator, reinforces the effects of multiple therapies against glioblastoma multiforme (GBM) in experimental settings. We analyzed MPS1 mRNA-expression in gliomas WHO grade II, III and in clinical subgroups of GBM. Data were obtained by qPCR analysis of tumor and healthy brain specimens and correlated with the patients’ clinical data. MPS1 was overexpressed in all gliomas on an mRNA level (ANOVA, p < 0.01) and correlated with tumor aggressiveness. We explain previously published conflicting results on survival: high MPS1 was associated with poorer long term survival when all gliomas were analyzed combined in one group (Cox regression: t < 24 months, p = 0.009, Hazard ratio: 8.0, 95% CI: 1.7–38.4), with poorer survival solely in low-grade gliomas (LogRank: p = 0.02, Cox regression: p = 0.06, Hazard-Ratio: 8.0, 95% CI: 0.9–66.7), but not in GBM (LogRank: p > 0.05). This might be due to their lower tumor volume at the therapy start. GBM patients with high MPS1 mRNA-expression developed clinical symptoms at an earlier stage. This, however, did not benefit their overall survival, most likely due to the more aggressive tumor growth. Since MPS1 mRNA-expression in gliomas was enhanced with increasing tumor aggressiveness, patients with the worst outcome might benefit best from a treatment directed against MPS1. KW - glioblastoma multiforme KW - low-grade glioma KW - astrocytoma KW - recurrence KW - multifocal growth KW - mRNA expression KW - MPS1 KW - TTK KW - therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236105 VL - 8 IS - 7 ER - TY - JOUR A1 - Weiland, Judith A1 - Beez, Alexandra A1 - Westermaier, Thomas A1 - Kunze, Ekkehard A1 - Sirén, Anna-Leena A1 - Lilla, Nadine T1 - Neuroprotective strategies in aneurysmal subarachnoid hemorrhage (aSAH) JF - International Journal of Molecular Sciences N2 - Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury. KW - subarachnoid hemorrhage (SAH) KW - inflammation KW - thromboinflammation KW - metabolism KW - neuroprotection KW - therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260755 SN - 1422-0067 VL - 22 IS - 11 ER - TY - JOUR A1 - Wang, Huiqiang A1 - Chen, Nanhai G. A1 - Minev, Boris R. A1 - Szalay, Aladar A. T1 - Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells JF - Journal of Translational Medicine N2 - Background: Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy. Methods: Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44\(^+\)CD24\(^+\)ESA\(^+\) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models. Results: We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44\(^+\)CD24\(^+\)ESA\(^+\) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44\(^+\)CD24\(^-\)ESA\(^+\) cells. Conclusions: Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors. KW - tumors KW - therapy KW - metastasis KW - identification KW - lines KW - gene expression KW - in-vitro propagation KW - acute myeloid leukemia KW - epithelial-mesenchymal transition KW - subpopulation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130019 VL - 10 IS - 167 ER -