TY - THES A1 - Hädrich, Dustin T1 - Schädeldachplastiken: Ein Vergleich zwischen freihand-modellierten- (Palacos®) und computer-assistiert hergestellten (CAD-CAM) - PMMA Implantaten T1 - Cranioplasty: A comparison between intraoperative-moulded (Palacos®) and computer-assisted manufactured (CAD-CAM) PMMA implants N2 - Einführung Die Kranioplastik (KP) nach Kraniektomie dient der Wiederherstellung der Funktionalität und Ästhetik des Schädels. Obwohl es sich um einen Routineeingriff handelt, wurden hohe Komplikationsraten beschrieben, die zum Teil auf die unterschiedlichen Arten des verwendeten Implantatmaterials zurückzuführen sind. Wir haben diese Studie durchgeführt, um intraoperativ-geformte (Palacos®) und CAD-CAM-PMMA-Implantate bei Patienten/-innen nach Kraniektomie hinsichtlich perioperativer Modalitäten, kurz- und langfristiger Komplikationsraten und ästhetischer Ergebnisse zu vergleichen. Methoden Diese retrospektive Single-Center-Analyse wurde an 350 Patienten mit 359 Kranioplastiken durchgeführt, die sich in 133 Palacos®-Fälle (01/2005-12/2012) und 226 CAD-CAM-Fälle (01/2010-12/2018) aufteilten. Postoperative Komplikationen wurden in kurzfristige (≤ 30 Tage) und langfristige (> 30 Tage) unterteilt. Die ästhetischen Ergebnisse wurden per Telefoninterview erhoben und auf einer 5-Punkte-Skala bewertet. Ergebnisse CAD-CAM-Patienten hatten eine kürzere Operationszeit (p < 0.001), einen geringeren intraoperativen Blutverlust (p < 0.001) und einen kürzeren postoperativen Krankenhausaufenthalt (p < 0.005) als Palacos®-Patienten. Operative Revisionen nach CP mussten bei 12,8 % der Patienten durchgeführt werden. Implantatinfektionen traten bei 3,8 % der Palacos®-Fälle und 1,8 % der CAD-CAM-Fälle auf. Wundheilungsstörungen traten bei CAD-CAM-Patienten häufiger auf, was mit einer höheren Anzahl an kraniellen Vor-Operationen und Vorinfektionen einherging. Palacos®-Patienten hatten signifikant mehr Implantatdislokationen (p < 0.05). CAD-CAM-Patienten berichteten von einem besseren ästhetischen Ergebnis im Vergleich zu Palacos®-Patienten. Fazit Diese Studie zeigt eine Überlegenheit der CAD-CAM-PMMA-Implantate im Vergleich zu Palacos®-Implantaten hinsichtlich peri- und postoperativer Faktoren, sowie dem ästhetischen Ergebnis. CAD-CAM-Implantate haben geringere Komplikations- und Infektionsraten als Palacos®-Implantate und zeigten positive Wirkungen, wenn sie in vorinfiziertes Gewebe implantiert wurden. Die langfristigen Komplikationsraten von CAD-CAM-Implantaten müssen weiter evaluiert werden. N2 - Introduction Cranioplasty (CP) after craniectomy restores the functionality and aesthetic of the patient’s cranial vault. Although it is a routine procedure, high complication rates have been described, partly related to the different type of implant material used. We conducted this study to compare intraoperative-moulded (Palacos®) and CAD-CAM-PMMA implants in patients underwent craniectomy regarding perioperative modalities, short- and long-term complication rates and aesthetic results. Methods This retrospective single-center-analysis was conducted on 350 patients with 359 cranioplasties, dividing into 133 Palacos® cases (01/2005-12/2012) and 226 CAD-CAM cases (01/2010-12/2018). Postoperative complications were divided into short-term (> 30 days) and long-term (< 30 days). Aesthetic results were evaluated via telephone interview on a 5-item scale. Results CAD-CAM patients had a shorter surgery time (p < 0.001), a lower intraoperative blood loss (p < 0.001) and shorter postoperative hospitalization (p < 0.005) than Palacos® patients. Operative revisions after CP had to be carried out at 12.8% of patients. Implant infections occurred in 3.8% of Palacos® cases and 1.8% of CAD-CAM cases. Wound healing disorders occurred more frequently in CAD-CAM patients, which was associated with higher cranial pre-operation and pre-infection rates. Palacos® patients had significantly more implant dislocations (p < 0.05). CAD-CAM patients reported a better aesthetic result compared to Palacos® patients. Conclusion This study shows superior peri-, postoperative and aesthetic results for CAD-CAM-implants compared to Palacos®. CAD-CAM implants have lower complication and infection rates than Palacos® implants and showed positive effects when implanted in pre-infected tissue. Long-term complication rates of CAD-CAM implant need to be further evaluated. KW - Schädelchirurgie KW - Trepanation KW - Polymethylmethacrylate KW - Kranioplastik KW - Komplikationen KW - PMMA KW - ästhetische Ergebnisse KW - cranioplasty KW - aesthetic results KW - complications KW - CAD-CAM KW - Komplikation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-289899 ER - TY - JOUR A1 - Binder, Tobias A1 - Lange, Florian A1 - Pozzi, Nicolò A1 - Musacchio, Thomas A1 - Daniels, Christine A1 - Odorfer, Thorsten A1 - Fricke, Patrick A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Capetian, Philipp T1 - Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson’s disease: a comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial JF - Brain Stimulation N2 - Highlights • Beta-Guided programming is an innovative approach that may streamline the programming process for PD patients with STN DBS. • While preliminary findings from our study suggest that Beta Titration may potentially mitigate STN overstimulation and enhance symptom control, • Our results demonstrate that beta-guided programming significantly reduces programming time, suggesting it could be efficiently integrated into routine clinical practice using a commercially available patient programmer. Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. Objective To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. Methods We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). Results All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). Conclusion Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice. KW - beta power KW - deep brain stimulation KW - local field potentials KW - Parkinson's disease KW - DBS programming KW - DBS biomarkers Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350280 VL - 16 IS - 5 ER - TY - JOUR A1 - Lisowski, Dominik A1 - Hartrampf, Philipp E. A1 - Hasenauer, Natalie A1 - Nickl, Vera A1 - Monoranu, Camelia-Maria A1 - Tamihardja, Jörg T1 - Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report JF - BMC Neurology N2 - Background Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis. Case presentation We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment. Conclusions E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients. KW - beta-catenin KW - E-cadherin KW - meningioma KW - peptide receptor radionuclide therapy (PRRT) KW - radiotherapy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357996 VL - 23 ER - TY - JOUR A1 - Breun, Maria A1 - Flock, Katharina A1 - Feldheim, Jonas A1 - Nattmann, Anja A1 - Monoranu, Camelia M. A1 - Herrmann, Pia A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten A1 - Stein, Ulrike T1 - Metastasis associated in colorectal cancer 1 (MACC1) mRNA expression is enhanced in sporadic vestibular schwannoma and correlates to deafness JF - Cancers N2 - Vestibular schwannoma (VS) are benign cranial nerve sheath tumors of the vestibulocochlear nerve. Their incidence is mostly sporadic, but they can also be associated with NF2-related schwannomatosis (NF2), a hereditary tumor syndrome. Metastasis associated in colon cancer 1 (MACC1) is known to contribute to angiogenesis, cell growth, invasiveness, cell motility and metastasis of solid malignant cancers. In addition, MACC1 may be associated with nonsyndromic hearing impairment. Therefore, we evaluated whether MACC1 may be involved in the pathogenesis of VS. Sporadic VS, recurrent sporadic VS, NF2-associated VS, recurrent NF2-associated VS and healthy vestibular nerves were analyzed for MACC1 mRNA and protein expression by quantitative polymerase chain reaction and immunohistochemistry. MACC1 expression levels were correlated with the patients’ clinical course and symptoms. MACC1 mRNA expression was significantly higher in sporadic VS compared to NF2-associated VS (p < 0.001). The latter expressed similar MACC1 concentrations as healthy vestibular nerves. Recurrent tumors resembled the MACC1 expression of the primary tumors. MACC1 mRNA expression was significantly correlated with deafness in sporadic VS patients (p = 0.034). Therefore, MACC1 might be a new molecular marker involved in VS pathogenesis. KW - vestibular schwannoma KW - metastasis associated in colorectal cancer 1 (MACC1) KW - pathogenesis KW - deafness KW - NF2-related schwannomatosis (NF2) KW - mRNA expression Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362543 SN - 2072-6694 VL - 15 IS - 16 ER - TY - THES A1 - Schulz, Ellina T1 - Lokale Ultraschall-vermittelte Zytostatika-Applikation zur Behandlung von Hirntumoren T1 - Local ultrasound mediated cytostatic drug application for the treatment of brain tumors N2 - Glioblastoma (GBM) sind bösartige hirneigene Tumore, deren schlechte Prognose einer innovativen Therapie bedarf. Aus diesem Grund wurde ein neuer Therapieansatz entwickelt, der auf einer lokalen Ultraschall-vermittelten Zytostatika Applikation beruht. Hierfür wurden stabile Microbubbles (MB) bestehend aus Phospholipiden synthetisiert. Es konnte gezeigt werden, dass MB als auch fokussierter Ultraschall niedriger Intensität (LIFU) keinen negativen Einfluss auf GBM-Zellen hat. MB hingegen konnten mittels LIFU destruiert werden, wodurch das in den MB eingeschlossene Chemotherapeutikum freigesetzt werden kann. Es wurden verschiedene Platin(II)- und Palladium(II)-Komplexe auf GBM Zellen getestet. Zur Beladung der MB wurde Doxorubicin (Dox) verwendet. Es konnte eine Beladungseffizienz der MB mit Dox von 52 % erreicht werden, auch eine Aufreinigung dieser mittel Ionenaustausch-Chromatographie und Dialyse war erfolgreich. Die Austestung der mit Dox beladenen MB (MBDox) erfolgte auf GBM-Zellen in 2D- und 3D-Zelkulturmodellen. Dabei zeigte sich, dass die Behandlung mit MBDox und LIFU für 48 h eine zytotoxische Wirkung hatte, die sich signifikant von der Behandlung mit MBDox ohne LIFU unterschied. Zur Austestung der MBDox in 3D-Zellkulturmodellen wurden zwei Scaffold-Systeme eingesetzt. Es zeigte sich in den Versuchen, dass MBDox mit LIFU im Vergleich zu MBDox ohne LIFU Applikation einen zytotoxischen Effekt auf GBM-Zellen haben. Somit konnte die Wirksamkeit der Zytostatika Applikation mittels MB und LIFU in 2D- und 3D-Zellkulturmodellen erfolgreich etabliert werden. Als weiterer Schritt wurden zwei 3D in vitro Modelle erarbeitet. Dabei wurden zunächst organotypische hippocampale Slice Kulturen (organotypic hippocampal brain slice cultures, OHSC) aus der Maus hergestellt und anschließend mit fluoreszent-markierten Mikrotumoren aus GBM-Zelllinien, Primärzellen (PZ) und aus Patienten generierten GBM-Organoiden hergestellt. Diese GBM-Modelle wurden mit Tumor Treating Fields (TTFields) behandelt. Dabei war eine Abnahme der Tumorgröße von Mikrotumoren aus GBM-Zellen und PZ unter TTFields-Behandlung für 72 h messbar. Als weiteres in vitro Modell wurden humane Tumorschnitte aus intraoperativ entferntem GBM-Patientenmaterial hergestellt. Die Schnitte wiesen ein heterogenes Ansprechen nach 72 h TTFields-Applikation auf. Dies spiegelt die Heterogenität des GBM sehr gut wider und bestärkt die Eignung des Modelles zur Untersuchung von neuen Therapieansätzen zur Behandlung von GBM. N2 - Glioblastoma (GBM) are malignant brain tumor with a poor prognosis requiring innovative therapy. For this reason, a new therapeutic approach based on local ultrasound-mediated cytostatic application is now being established. For this purpose, stable microbubbles (MB) consisting of phospholipids were synthesized. It could be shown that MB as well as focused low intensity ultrasound (LIFU) had no negative effect on GBM cells. MB, on the other hand, could be destroyed by LIFU, allowing the release of the chemotherapeutic agent entrapped in MB. Different platinum(II) and palladium(II) complexes were tested on GBM cells. Doxorubicin (Dox) was used to load the MB. Loading efficiency of MB with Dox of 52% was achieved, and purification of these by ion-exchange chromatography and dialysis was also successful. Dox-loaded MB (MBDox) was tested on GBM cells in 2D and 3D cell culture models. This showed that treatment with MBDox and LIFU for 48 h had a cytotoxic effect that was significantly different from treatment with MBDox without LIFU. Two scaffold systems were used to test MBDox in 3D cell culture models. It was shown in the experiments that MBDox with LIFU had a cytotoxic effect on GBM cells compared with MBDox without LIFU application. Thus, the efficacy of cytostatic drug application using MB and LIFU was successfully established in 2D and 3D cell culture models. As a further step, two 3D in vitro models were developed. Here, organotypic hippocampal brain slice cultures (OHSC) were first prepared from mice and then with fluorescent-labeled microtumors from GBM cell lines, primary cells (PZ), and GBM organoids generated from patients. These GBM models were treated with tumor treating fields (TTFields). Thereby, a decrease in tumor size of microtumors derived from GBM cells and PZ was measurable under TTFields treatment for 72 h. As another in vitro model, human tumor sections were prepared from intraoperatively removed GBM patient material. The sections showed heterogeneous responses after 72 h of TTFields application. This reflects the heterogeneity of GBM very well and reinforces the suitability of the model to investigate new therapeutic approaches for the treatment of GBM. KW - Glioblastom KW - Hirntumor KW - Ultraschall KW - Microbubbles KW - Glioblastoma KW - Slice Culture KW - 3D cell culture Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320168 ER - TY - JOUR A1 - Mrestani, Achmed A1 - Lichter, Katharina A1 - Sirén, Anna-Leena A1 - Heckmann, Manfred A1 - Paul, Mila M. A1 - Pauli, Martin T1 - Single-molecule localization microscopy of presynaptic active zones in Drosophila melanogaster after rapid cryofixation JF - International Journal of Molecular Sciences N2 - Single-molecule localization microscopy (SMLM) greatly advances structural studies of diverse biological tissues. For example, presynaptic active zone (AZ) nanotopology is resolved in increasing detail. Immunofluorescence imaging of AZ proteins usually relies on epitope preservation using aldehyde-based immunocompetent fixation. Cryofixation techniques, such as high-pressure freezing (HPF) and freeze substitution (FS), are widely used for ultrastructural studies of presynaptic architecture in electron microscopy (EM). HPF/FS demonstrated nearer-to-native preservation of AZ ultrastructure, e.g., by facilitating single filamentous structures. Here, we present a protocol combining the advantages of HPF/FS and direct stochastic optical reconstruction microscopy (dSTORM) to quantify nanotopology of the AZ scaffold protein Bruchpilot (Brp) at neuromuscular junctions (NMJs) of Drosophila melanogaster. Using this standardized model, we tested for preservation of Brp clusters in different FS protocols compared to classical aldehyde fixation. In HPF/FS samples, presynaptic boutons were structurally well preserved with ~22% smaller Brp clusters that allowed quantification of subcluster topology. In summary, we established a standardized near-to-native preparation and immunohistochemistry protocol for SMLM analyses of AZ protein clusters in a defined model synapse. Our protocol could be adapted to study protein arrangements at single-molecule resolution in other intact tissue preparations. KW - active zone KW - nanotopology KW - neuromuscular junction KW - high-pressure freezing/freeze substitution KW - PFA in ethanol KW - dSTORM KW - Drosophila melanogaster Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304904 SN - 1422-0067 VL - 24 IS - 3 ER - TY - JOUR A1 - Vergote, Ignace A1 - Macarulla, Teresa A1 - Hirsch, Fred R. A1 - Hagemann, Carsten A1 - Miller, David Scott T1 - Tumor Treating Fields (TTFields) therapy concomitant with taxanes for cancer treatment JF - Cancers N2 - Non-small cell lung cancer, ovarian cancer, and pancreatic cancer all present with high morbidity and mortality. Systemic chemotherapies have historically been the cornerstone of standard of care (SOC) regimens for many cancers, but are associated with systemic toxicity. Multimodal treatment combinations can help improve patient outcomes; however, implementation is limited by additive toxicities and potential drug–drug interactions. As such, there is a high unmet need to develop additional therapies to enhance the efficacy of SOC treatments without increasing toxicity. Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. The therapy is locoregional and is delivered noninvasively to the tumor site via a portable medical device that consists of field generator and arrays that are placed on the patient’s skin. As a noninvasive treatment modality, TTFields therapy-related adverse events mainly consist of localized skin reactions, which are manageable with effective acute and prophylactic treatments. TTFields selectively target cancer cells through a multi-mechanistic approach without affecting healthy cells and tissues. Therefore, the application of TTFields therapy concomitant with other cancer treatments may lead to enhanced efficacy, with low risk of further systemic toxicity. In this review, we explore TTFields therapy concomitant with taxanes in both preclinical and clinical settings. The summarized data suggest that TTFields therapy concomitant with taxanes may be beneficial in the treatment of certain cancers. KW - Tumor Treating Fields (TTFields) KW - taxanes KW - non-small cell lung cancer (NSCLC) KW - ovarian cancer KW - pancreatic cancer KW - mechanism of action Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305007 SN - 2072-6694 VL - 15 IS - 3 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Köppl, Theresa A1 - Hörmann, Julia A1 - Schönhärl, Sebastian A1 - Bugaeva, Polina A1 - Kessler, Almuth F. A1 - Burek, Malgorzata A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier JF - Pharmaceutics N2 - In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies. KW - blood-brain barrier KW - Tumor-Treating Fields (TTFields) KW - CNS disorders KW - human brain microvascular endothelial cells (HBMVEC) KW - human cells KW - 3D in vitro model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304830 SN - 1999-4923 VL - 15 IS - 1 ER - TY - THES A1 - Herbinger, Anna Maria T1 - Wirkungsverstärkung von Vincristin und Paclitaxel auf Glioblastomzellen durch TTFields T1 - Enhancement of effect of vincristine and paclitaxel on glioblastoma cells by TTFields N2 - Das Glioblastom (GBM) ist der häufigste maligne primäre Hirntumor im Erwachsenenalter und geht mit einer infausten Prognose einher. Die Standardtherapie bei Erstdiagnose besteht aus Tumorresektion gefolgt von kombinierter Radiochemotherapie mit Temozolomid nach Stupp-Schema. Eine neue Therapieoption stellen die Tumor Treating Fields (TTFields) in Form lokal applizierter elektrischer Wechselfelder dar. Mit dem Einsatz der TTFields kann durch Störung der mitotischen Abläufe die Zellproliferation von Tumorzellen gehemmt und dadurch das Gesamtüberleben im Vergleich zur alleinigen Radiochemotherapie nachweislich deutlich verlängert werden. Auch verschiedene Chemotherapeutika, die bereits klinisch eingesetzt werden, greifen in den Ablauf der Mitose ein. So auch die Zytostatika Vincristin (VIN) und Paclitaxel (PTX), die durch einen gegensätzlichen Mechanismus durch Destabilisierung bzw. Stabilisierung von Mikrotubulistrukturen ihre Wirkung entfalten. Die Frage, ob eine Verstärkung dieser Wirkung durch den kombinierten Einsatz mit TTFields erreicht werden kann, wurde in dieser Arbeit an den beiden GBM-Zelllinien U87 und GaMG untersucht. Zunächst wurde mit dem xCELLigence-Systems über eine Real-Time-Impedanzmessung für diese beiden Chemotherapeutika jeweils die mittlere effektive Dosis (EC50-Wert), bei der ein halbmaximaler Effekt auftritt, spezifisch für jede Zelllinie bestimmt. Diese betrug bei VIN durchschnittlich 200nM für die Zelllinie U87 bzw. 20nM für die Zelllinie GaMG und lag für PTX bei 60nM für beide Zelllinien. Mit diesen Dosierungen wurden die beiden Zelllinien allein und in Kombination mit TTFields über 72h behandelt. Anschließend wurde die Zellproliferation analysiert und mit unbehandelten Tumorzellen verglichen. Während jeder Behandlungsarm einzeln eine signifikante Wirkung gegenüber der unbehandelten Vergleichsgruppe zeigte, hatte weder die Kombination von TTFields mit VIN noch mit PTX in den untersuchten Dosierungen einen zusätzlichen signifikanten Nutzen. Es besteht weiterer Forschungsbedarf zum kombinierten Einsatz von TTFields mit anderen Therapieformen. N2 - Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and is associated with an infavorable prognosis. Standard therapy at initial diagnosis consists of tumor resection followed by combined radiochemotherapy with temozolomide according to the Stupp regimen. Tumor Treating Fields (TTFields) in the form of locally applied alternating electric fields represent a new therapeutic option. With the use of TTFields, cell proliferation of tumor cells can be inhibited by interfering with mitotic processes, which has been shown to significantly prolong overall survival compared to radiochemotherapy alone. Various chemotherapeutic treatments already in clinical use also interfere with mitotic processes. This is also the case with the cytostatic drugs vincristine (VIN) and paclitaxel (PTX), which exert their effects by an opposing mechanism through destabilization and stabilization of microtubule structures. The question whether an enhancement of this effect can be achieved by combined use with TTFields was investigated in this work using the two GBM cell lines U87 and GaMG. First, using the xCELLigence system via real-time impedance measurement, the mean effective dose (EC50-value) at which a half-maximal effect occurs was determined for each of these two chemotherapeutic agents specifically for each cell line. This was averaged 200nM for VIN for the U87 cell line and 20nM for the GaMG cell line, and was 60nM for PTX for both cell lines. The two cell lines were treated with these doses alone and in combination with TTFields for 72h. Cell proliferation was then analyzed and compared to untreated tumor cells. While each treatment individually showed a significant effect compared with the untreated control group, neither the combination of TTFields with VIN nor with PTX had any additional significant benefit at the doses studied. Further research is needed on the combined use of TTFields with other therapies. KW - Tumortherapiefelder KW - Vincristin KW - Taxol KW - TTFields KW - Paclitaxel KW - glioblastoma KW - tumor treating fields KW - vincristine KW - paclitaxel KW - Glioblastom Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-329836 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Kessler, Almuth F. A1 - Feldheim, Julia J. A1 - Schmitt, Dominik A1 - Oster, Christoph A1 - Lazaridis, Lazaros A1 - Glas, Martin A1 - Ernestus, Ralf-Ingo A1 - Monoranu, Camelia M. A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - BRMS1 in gliomas — an expression analysis JF - Cancers N2 - The metastatic suppressor BRMS1 interacts with critical steps of the metastatic cascade in many cancer entities. As gliomas rarely metastasize, BRMS1 has mainly been neglected in glioma research. However, its interaction partners, such as NFκB, VEGF, or MMPs, are old acquaintances in neurooncology. The steps regulated by BRMS1, such as invasion, migration, and apoptosis, are commonly dysregulated in gliomas. Therefore, BRMS1 shows potential as a regulator of glioma behavior. By bioinformatic analysis, in addition to our cohort of 118 specimens, we determined BRMS1 mRNA and protein expression as well as its correlation with the clinical course in astrocytomas IDH mutant, CNS WHO grade 2/3, and glioblastoma IDH wild-type, CNS WHO grade 4. Interestingly, we found BRMS1 protein expression to be significantly decreased in the aforementioned gliomas, while BRMS1 mRNA appeared to be overexpressed throughout. This dysregulation was independent of patients’ characteristics or survival. The protein and mRNA expression differences cannot be finally explained at this stage. However, they suggest a post-transcriptional dysregulation that has been previously described in other cancer entities. Our analyses present the first data on BRMS1 expression in gliomas that can provide a starting point for further investigations. KW - glioblastoma KW - metastasis KW - suppressor KW - behavior KW - mRNA KW - protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319225 SN - 2072-6694 VL - 15 IS - 11 ER - TY - JOUR A1 - Nickl, Vera A1 - Eck, Juliana A1 - Goedert, Nicolas A1 - Hübner, Julian A1 - Nerreter, Thomas A1 - Hagemann, Carsten A1 - Ernestus, Ralf-Ingo A1 - Schulz, Tim A1 - Nickl, Robert Carl A1 - Keßler, Almuth Friederike A1 - Löhr, Mario A1 - Rosenwald, Andreas A1 - Breun, Maria A1 - Monoranu, Camelia Maria T1 - Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma JF - Cancers N2 - While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future. KW - glioblastoma KW - organoids KW - slice culture KW - tumormicroenvironment Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319249 SN - 2072-6694 VL - 15 IS - 10 ER - TY - JOUR A1 - Paul, Mila M. A1 - Mieden, Hannah J. A1 - Lefering, Rolf A1 - Kupczyk, Eva K. A1 - Jordan, Martin C. A1 - Gilbert, Fabian A1 - Meffert, Rainer H. A1 - Sirén, Anna-Leena A1 - Hoelscher-Doht, Stefanie T1 - Impact of a femoral fracture on outcome after traumatic brain injury — a matched-pair analysis of the TraumaRegister DGU\(^®\) JF - Journal of Clinical Medicine N2 - Traumatic brain injury (TBI) is the leading cause of death and disability in polytrauma and is often accompanied by concomitant injuries. We conducted a retrospective matched-pair analysis of data from a 10-year period from the multicenter database TraumaRegister DGU\(^®\) to analyze the impact of a concomitant femoral fracture on the outcome of TBI patients. A total of 4508 patients with moderate to critical TBI were included and matched by severity of TBI, American Society of Anesthesiologists (ASA) risk classification, initial Glasgow Coma Scale (GCS), age, and sex. Patients who suffered combined TBI and femoral fracture showed increased mortality and worse outcome at the time of discharge, a higher chance of multi-organ failure, and a rate of neurosurgical intervention. Especially those with moderate TBI showed enhanced in-hospital mortality when presenting with a concomitant femoral fracture (p = 0.037). The choice of fracture treatment (damage control orthopedics vs. early total care) did not impact mortality. In summary, patients with combined TBI and femoral fracture have higher mortality, more in-hospital complications, an increased need for neurosurgical intervention, and inferior outcome compared to patients with TBI solely. More investigations are needed to decipher the pathophysiological consequences of a long-bone fracture on the outcome after TBI. KW - traumatic brain injury KW - femoral fracture KW - damage control orthopedics KW - mortality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319363 SN - 2077-0383 VL - 12 IS - 11 ER - TY - JOUR A1 - Schadt, Fabian A1 - Israel, Ina A1 - Beez, Alexandra A1 - Alushi, Kastriot A1 - Weiland, Judith A1 - Ernestus, Ralf-Ingo A1 - Westermaier, Thomas A1 - Samnick, Samuel A1 - Lilla, Nadine T1 - Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days JF - Scientific Reports N2 - Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-[18F]Fluoro-2-deoxy-glucose ([\(^{18}\)F]FDG) was evaluated in different brain regions in 14 male Sprague–Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial [\(^{18}\)F]FDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher [\(^{18}\)F]FDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This [\(^{18}\)F]FDG-PET study provides important insights into glucose metabolism alterations following SAH—for the first time in different brain regions and up to day 7 during course of disease. KW - SAH KW - metabolism KW - brain Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300725 VL - 13 IS - 1 ER - TY - THES A1 - Lichter, Katharina T1 - Die Ultrastruktur von Aktiven Zonen in hippocampalen Moosfaserboutons T1 - The ultrastructure of active zones in hippocampal mossy fiber boutons N2 - In nervous systems, synapses precisely orchestrate information transfer and memory formation. Active zones (AZ) are specialized subcellular compartments at the presynaptic mesoscale which process synaptic transmission on an ultrastructural level. The AZ cytomatrix including the essential scaffold protein Rab3 interacting molecule (RIM) enables exocytosis of synaptic vesicles. A deficiency of the locally most abundant protein isoform RIM1α diminishes long-term potentiation in a complex central mammalian synapse – the connection of hippocampal mossy fiber boutons (MFB) to cornu ammonis (CA)3 pyramidal neurons. Behaviourally, these mice present with learning impairment. The present MD thesis addresses the so far unknown three-dimensional (3D) AZ ultrastructure of MFBs in acute hippocampal slices of wild-type and RIM1α-/- mice. In a first set of experiments, a standardized protocol for near-to-native synaptic tissue preparation at MFBs using high-pressure freezing and freeze substitution and 3D modelling using electron tomography was developed and established. Based on the excellent preservation of synaptic tissue using this protocol, the AZ ultrastructure in both genotypes was quantified in detail up to an individual docked synaptic vesicle using custom-written programming scripts. The experiments demonstrate that deficiency of RIM1α leads to multidimensional alter-ation of AZ 3D ultrastructure and synaptic vesicle pools in MFBs. (Tightly) docked synaptic vesicles – ultrastructural correlates of the readily releasable pool – are reduced, decentralized, and structurally modified, whereas the more distant vesicle pool clusters more densely above larger and more heterogenous AZ surfaces with higher synaptic clefts. The present thesis contributes to a more comprehensive understanding regarding the role of RIM1α for (tight) vesicle docking and organization at MFBs. Furthermore, the precise 3D ultrastructural analysis of MFB AZs in this thesis provides the necessary mor-phological basis for further studies to correlate synaptic ultrastructure with presynaptic plasticity and memory dysfunction in RIM1α-/- mice using advanced electrophysiological and behavioral techniques. N2 - In Nervensystemen bedürfen Informationsweitergabe und Gedächtnisformation eines präzisen Zusammenspiels von Synapsen in Zeit und Raum. Synaptische Transmission basiert strukturell auf mesoskopischen cytosolischen Kompartimenten an der präsynaptischen Membran, sogenannten Aktiven Zonen (AZ). Ihre Cytomatrix, bestehend aus zentralen Gerüstproteinen wie Rab3 interacting molecule (RIM), ermöglicht eine schnelle Freisetzung synaptischer Vesikel. Die Defizienz der lokal häufigsten Isoform RIM1α resultiert an einer komplexen zentralen Säugersynapse, die des hippocampalen Moosfaserboutons (MFB) zu im Cornu ammonis (CA)3 befindlichen Pyramidalzellen, in einer dezimierten Langzeitplastizität. Auf Verhaltensebene zeigen diese Mäuse eine reduzierte Lernfähigkeit. Die vorliegende Dissertation widmet sich grundlegend der bisher unbekannten dreidimensionalen (3D) AZ-Ultrastruktur des MFB in akuten Hippocampusschnitten der adulten Wildtyp- und RIM1α-Knock-Out-Maus (RIM1α\(^{-/-}\)). In einer methodischen Entwicklungsphase wurde ein neuartiges, anspruchsvolles Protokoll der nahezu artefaktfreien (near to native) Synapsenpräparation am MFB mittels Hochdruckgefrierung und Gefriersubstitution sowie der 3D-Modellierung mittels Elektronentomographie etabliert. In einer zweiten Experimentier- und Analysephase ermöglichte die hochwertige synaptische Gewebeerhaltung in beiden Genotypen eine standardisierte, auf Programmierskripten basierte Quantifizierung der AZ-Ultrastruktur bis auf die Ebene eines individuell gedockten synaptischen Vesikels. Dieser Dissertation gelingt der Nachweis, dass eine Defizienz von RIM1α zu einer multidimensionalen ultrastrukturellen Veränderung der AZ und ihres Vesikelpools am MFB führt. Neben einer Reduktion, Dezentralisierung und strukturellen Veränderung (eng) gedockter Vesikel – der ultrastrukturellen Messgrößen von unmittelbar freisetzungsfähigen Vesikeln – verdichtet sich der distaler lokalisierte Vesikelpool auf zugleich größeren, heterogenen AZ-Flächen mit erweitertem synaptischem Spalt. Vorliegende Untersuchungen tragen zum Verständnisgewinn über eine zentrale Rolle von RIM1α für das Docking und die Organisation von Vesikeln der AZ im MFB bei. Darüber hinaus stellen die präzisen ultrastrukturellen Analysen eine morphologische Grundlage für weiterführende Studien mit Hilfe modernster Techniken dar, beispielsweise über die Auswirkungen der geänderten RIM1α\(^{-/-}\) AZ-Ultrastruktur auf die präsynaptische Plastizität sowie in Korrelation zum Gedächtnis und Lernen der Tiere. KW - Hippocampus KW - Neurowissenschaften KW - Exzitatorische Synapse KW - Synaptische Transmission KW - Synaptische Vesikel KW - active zone KW - presynaptic KW - mossy fiber synapse KW - RIM1α KW - CA3 KW - high-pressure freezing/freeze substitution KW - electron tomography KW - acute brain slices Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303126 ER - TY - THES A1 - Stollburges, Elisa T1 - Therapeutisches Potential der IL-1ß-Neutralisierung nach Schädel-Hirn-Trauma - eine präklinische randomisierte Kontrollstudie T1 - The therapeutic potential of interleukin 1 beta neutralisation treating Traumatic Brain injury - A preclinical randomised control study N2 - Durch die Interleukin 1ß Neutralisierung mittels eines Antikörpers soll versucht werden, das Outcome nach einem Schädelhirntrauma zu verbessern und den erlittenen Schaden zu minimieren N2 - With the support of antibodies, interleukin 1 beta neutralisation attempts to improve the outcome after suffering from a traumatic brain injury and to limit the damage suffered KW - Interleukin 1-beta KW - Interleukin 1 beta Neutralisierung KW - Schädel-Hirn-Trauma Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349346 ER -