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 - Jakob, Peter A1 - Hertlein, Tobias A1 - Sturm, Volker A1 - Kircher, Stefan A1 - Basse-Lüsebrink, Thomas A1 - Haddad, Daniel A1 - Ohlsen, Knut T1 - Visualization of Abscess Formation in a Murine Thigh Infection Model of Staphylococcus aureus by 19F-Magnetic Resonance Imaging (MRI) N2 - Background: During the last years, 19F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent based MRI 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 19F-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 - Staphylococcus aureus Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-74994 ER - TY - THES A1 - Sturm, Volker Jörg Friedrich T1 - \(^{19}F\) Magnetresonanztomographie zur Bildgebung von Infektionen im Zeitverlauf T1 - \(^{19}F\) magnetic resonance imaging to monitor the timecourse of bacterial infections in vivo N2 - Im Rahmen dieser Arbeit sollten die Möglichkeiten der MR Tomographie erkundet werden bakterielle Infektionen im Zeitverlauf darzustellen. Genauer gesagt sollte das Potential der MR Tomographie anhand eines durch eine Infektion induzierten lokalisierten Abszesses unter Verwendung dreier unterschiedlicher MRT Methoden untersucht werden: Mittels nativem \(T_2\) Kontrast; der Verwendung von superparamagnetischen Eisenoxid Partieln (USPIO) als \(T_2^*\) Kontrastmittel; und dem Einsatz von Perfluorkarbonen (PFC) als \(^{19}F\) MRT Marker (siehe Kapitel 3). Wie erwartet führte die durch die Infektion hervorgerufene Entzündung zu veränderten \(T_2\)-Zeiten, welche auf \(T_2\)-gewichteten MR Bildern eine Lokalisierung des Abszessbereiches erlauben. Jedoch eigneten sich diese Daten aufgrund der graduellen Änderung der \(T_2\)-Zeiten nicht, um eine klare Grenze zwischen Abszess und umliegendem Gewebe zu ziehen. Superparamagnetische Eisenoxidpartikel andererseit haben als MRT Kontrastmittel bereits in den letzten Jahren ihre Fähigkeit unter Beweis gestellt Entzündungen [53, 58, 64] darzustellen. Die Anreicherung dieser Partikel am Rande des Abszesses [53], wie sie auch in unseren MR Daten zu beobachten war, erlaubte eine relativ scharfe Abgrenzung gegenüber dem umgebenden Gewebe in der chronischen Phase der Infektion (Tag 9 p.i.). Hingegen genügte die nur sehr spärlichen Anreicherung von USPIO Partikeln in der akuten Phase der Infektion (Tag 3 p.i.) nicht für eine entsprechende Abgrenzung [58]. Aufgrund der sehr geringen biologischen Häufigkeit und den sehr kurzen Relaxationszeiten von endogenem Fluor eignen sich Perfluorkarbone als Markersubstanz in der MR Tomographie von biologischen Systemen. Insbesondere da PFC Emulsionen durch phagozytierende Zellen aufgenommen werden und im Bereich von Entzündungen akkumulieren [30, 59]. In dieser Arbeit konnte anhand der erhaltenen MRT Daten eine Akkumulation von Perfluorkarbonen nicht nur in der chronischen Phase, sondern auch in der akuten Phase nachgewiesen werden. Diese Daten erlauben somit zu allen untersuchten Zeitpunkten eine Abgrenzung zwischen Infektion und umliegenden Gewebe. Aufgrund der besagten Vorteile wurden die Perfluorkarbone gewählt, um die Möglichkeiten der MR Tomographie zu testen, quantitative Informationen über die schwere der Infektion zu liefern. Als Referenz für die Bakterienbelastung wurden die Biolumineszenzbildgebung (BLI) [49, 50] und die Standardmethode zur Bestimmung der Bakterienbelastung cfu (koloniebildenden Einheiten) herangezogen. Eine Gegenüberstellung der zeitlichen Verläufe der durch die Biolumineszenzbildgebung und durch die cfu erhaltenen Daten liefert eine qualitative Übereinstimmung mit den durch die 19F MR Tomographie erhaltenen Daten. Dies trifft hierbei sowohl auf die über den gesamten Infektionsbereich hinweg summierten Signalamplituden, als auch auf das Volumen zu, in dem Fluor am Ort der Infektion akkumuliert wurde. Im Gegensatz zur Methode der cfu Bestimmung sind die MR Tomographie und die Biolumineszenzbildgebung nicht invasiv und erlauben die Verfolgung des Infektionsverlaufes an einem einzelnen Individuum. Hierzu benötigt, im Gegensatz zur MR Tomographie, die Methode der Biolumineszenzbildgebung jedoch einen speziellen Pathogenstamm. Darüber hinaus ist hervorzuheben, dass die MR Tomographie zudem die Möglichkeit bietet auch morphologische Informationen über den Infektionsbereich und seine Umgebung zu akquirieren. Gerade weil jede dieser Methoden die mit der Infektion einhergehenden Prozesse aus einer leicht anderen Blickrichtung betrachtet, erscheint es sinnvoll diese etablierte Untersuchungsplattform bestehend aus MRT, BLI und cfu über die in dieser Arbeit bearbeitete Fragestellung hinaus näher zu untersuchen. Insbesondere der Aspekt inwieweit die drei Methoden sich gegenseitig ergänzen, könnte einen tieferen Einblick in die Wechselwirkung zwischen Pathogen und Wirt erlauben. Auch wenn für die betrachtete Fragestellung bereits der hierdurchgeführte semiquanitative Ansatz zur Bestimmung der relativen Fluormengen am Ort der Infektion ausreichte, so ist doch im Allgemeinen wünschenswert probenbezogen die Sensitivität der Spule und damit die Güte der Spulenabstimmung zu bestimmen. Hierzu ist jedoch die Aufnahme von \(B_1\)-Karten unabdingbar und wird entsprechend im Kapitel 4 \(Bloch-Siegert B_1^+-Mapping\) näher addressiert. Der Schwerpunkt liegt hierbei, wie der Kapitelname bereits andeutet, auf der Bloch-Siegert Methode, die insbesondere in der präsentierten Implementierung in einer Turbo/ Multi Spin Echo Sequenz eine effiziente Nutzung der relativ langen \(T_\)2-Zeiten der Perfluorkarbone erlaubt. Da zudem die Bloch-Siegert-Methode eine rein phasenbasierte Methode ist, kann neben der aus den Daten erzeugten \(B_1\)-Karte zugleich ein unverfälschtes Magnitudenbild generiert werden, wodurch eine sehr effiziente Nutzung der vorhandenen Messzeit ermöglicht wird. Diese Eigenschaft ist insbesondere für \(^{19}F\) Bildgebung von besonderem Interesse, da hier für jede Messung, aufgrund der üblicherweise relativ geringen Konzentration an Fluoratomen, lange Messzeiten benötigt werden. Zusammenfassend konnte anhand des untersuchten Tiermodells sowohl die Fähigkeit der MR Tomographie nachgewiesen werden Infektionen im Zeitverlauf darzustellen, als auch die Fähigkeit der MR Tomographie quantitative Informationen über den Verlauf der Infektion zu liefern. Desweiteren konnte eine Möglichkeit aufgezeigt werden, welche das Potential hat in vertretbarem Zeitrahmen auch in vivo B1+-Karten auf dem Fluorkanal zu erstellen und so einen zentralen Unsicherheitsfaktor, für Relaxometry und absolute Quantifizierung von \(^{19}F\) Daten in vivo, zu beseitigen. N2 - The main focus of this work is to investigate the potential of magnetic resonance imaging (MRI) to monitor the timecourse of bacterial infections in vivo. More specifically, it focuses on the ability to localize and assess an infection-induced localized bulky abscess using three different MRI methods: the utilization of native \(T_2\) contrast; the usage of super paramagnetic iron oxide nanoparticles (USPIO) as MRI \(T_2^*\) contrast agents; and the application of perfluorcarbons (PFC) as \(^{19}F\) MRI marker (see chapter 3). Study results demonstrated that, as expected the altered \(T_2\) values present in the abscess area permit localization of the infection when using \(T_2\) weighted data. The precise boundary of the abscess, however, could not be determined due to the gradual change of the \(T_2\) values in the area of the infection. Conforming to other studies [53, 58], the MR-detected accumulation of USPIO particles along the abscess rim allowed definition of a fairly exact demarcation line between the abscess and surrounding tissue during the chronic phase of the infection (day 9 p.i.). During the acute phase of the infection (day 3 p.i.), however, the particle accumulation at the abscess rim was too sparse for precise boundary definition [58]. Because of their extremely low biological abundance and the very short relaxation times of endogenous fluorine, PFCs can be imaged background-free in a biological system. Moreover, as emulsified PFCs were taken up by phagocytosing cells and accumulated at the site of inflammation [30, 59], the acquired MRI data showed PFC accumulation during both the chronic and acute phases of infection. It was thus possible to differentiate between the abscess and surrounding tissue at each examined time point. Due to the described advantages, PFCs were chosen to evaluate with MRI the infection severity. As a bacterial burden reference, colony forming units (cfu) and bioluminescence imaging (BLI) [49, 50] were selected. Observation of BLI, cfu and \(^{19}F\) MRI data showed qualitative correlation during the investigated time course. This was true for the accumulated \(^{19}F\) MR signal in the area of infection and for the \(^{19}F\) MR signal volume. Additionally, unlike the cfu method MRI and BLI are non-invasive and thus data can be gathered at multiple time points. However, contrary to BLI, MRI does not require a special pathogen strain. Moreover, it can provide morphological data from an abscess and the surrounding tissue. Because the data delivered by each of these three methods (MRI, BLI and cfu), are based on alternative approaches, additional examinations of the established platform are suggested. For example, the extent to which the methods supplement each other may provide deeper insight into the interaction between pathogen and host. Even though the chosen semi quantitative approach was sufficient in the context of the evaluated issues to estimate the relative fluorine amount at the site of infection, it is in general desirable for each quantification to determine the sensitivity of the coil per sample. To address this issue the Bloch Siegert (BS) based \(B_1\) mapping method implemented in a turbo/ multi spin echo (TSE/MSE) sequence is presented in Chapter 4 Bloch-Siegert \(B_1^+\)-Mapping. Such a sequence allows effective use of the relatively long PFC \(T_2\) times and encodes BS information solely into the phase data. Thus, a \(B_1\) map can be created in addition to the unaltered TSE/MSE magnitude image. In the context of \(^{19}F\) imaging, this is of special interest due to the usually low amounts of fluorine resulting in long measurement times. In conclusion, it was shown that MRI not only enables visualization of the temporal behavior of infections on the investigated animal model, but it can also provide quantitative information about the progress of the infection. Additionally, a method potentially allowing in vivo B1+ mapping was introduced. This is an important step to improve the reliability of relaxometry and absolute quantification of in vivo \(^{19}F\) MRI. KW - Kernspintomografie KW - Bakterielle Infektion KW - 19F MR KW - Perfluorkarbon KW - Infektionsbildgebung KW - Bloch Siegert KW - B1 Mapping KW - Kontrastmittel Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122851 ER - TY - JOUR A1 - Weibel, Stephanie A1 - Basse-Luesebrink, Thomas Christian A1 - Hess, Michael A1 - Hofmann, Elisabeth A1 - Seubert, Carolin A1 - Langbein-Laugwitz, Johanna A1 - Gentschev, Ivaylo A1 - Sturm, Volker Jörg Friedrich A1 - Ye, Yuxiang A1 - Kampf, Thomas A1 - Jakob, Peter Michael A1 - Szalay, Aladar A. T1 - Imaging of Intratumoral Inflammation during Oncolytic Virotherapy of Tumors by \(^{19}\)F-Magnetic Resonance Imaging (MRI) JF - PLoS ONE N2 - Background Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate \(^{19}\)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy. Methodology/Principal Findings The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by \(^1H\)/\(^{19}\)F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the \(^{19}\)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the \(^{19}\)F signal hot spots and \(CD68^+\)-macrophages. Thereby, the \(CD68^+\)-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the \(^{19}\)F signal correlated with the extent of viral spreading within tumors. Conclusions/Significance These results suggest \(^{19}\)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, \(^{19}\)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response. KW - inflammation KW - fluorescence microscopy KW - oncolytic viruses KW - fluorescence imaging KW - macrophages KW - magnetic resonance imaging KW - histology KW - in vivo imaging Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130311 VL - 8 IS - 3 ER - TY - JOUR A1 - Hertlein, Tobias A1 - Sturm, Volker A1 - Jakob, Peter A1 - Ohlsen, Knut T1 - \(^{19}\)F Magnetic Resonance Imaging of Perfluorocarbons for the Evaluation of Response to Antibiotic Therapy in a Staphylococcus aureus Infection Model JF - PLoS ONE N2 - Background The emergence of antibiotic resistant bacteria in recent decades has highlighted the importance of developing new drugs to treat infections. However, in addition to the design of new drugs, the development of accurate preclinical testing methods is essential. In vivo imaging technologies such as bioluminescence imaging (BLI) or magnetic resonance imaging (MRI) are promising approaches. In a previous study, we showed the effectiveness of \(^{19}\)F MRI using perfluorocarbon (PFC) emulsions for detecting the site of Staphylococcus aureus infection. In the present follow-up study, we investigated the use of this method for in vivo visualization of the effects of antibiotic therapy. Methods/Principal findings Mice were infected with S. aureus Xen29 and treated with 0.9% NaCl solution, vancomycin or linezolid. Mock treatment led to the highest bioluminescence values during infection followed by vancomycin treatment. Counting the number of colony-forming units (cfu) at 7 days post-infection (p.i.) showed the highest bacterial burden for the mock group and the lowest for the linezolid group. Administration of PFCs at day 2 p.i. led to the accumulation of \(^{19}\)F at the rim of the abscess in all mice (in the shape of a hollow sphere), and antibiotic treatment decreased the \(^{19}\)F signal intensity and volume. Linezolid showed the strongest effect. The BLI, cfu, and MRI results were comparable. Conclusions \(^{19}\)F-MRI with PFCs is an effective non-invasive method for assessing the effects of antibiotic therapy in vivo. This method does not depend on pathogen specific markers and can therefore be used to estimate the efficacy of antibacterial therapy against a broad range of clinically relevant pathogens, and to localize sites of infection. KW - staphylococcus aureus KW - abscesses KW - vancomycin KW - antibiotics KW - magnetic resonance imaging KW - emulsions KW - bioluminescence imaging KW - in vivo imaging Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130113 VL - 8 IS - 5 ER - TY - JOUR A1 - El Majdoub, Faycal A1 - Hunsche, Stefan A1 - Igressa, Alhadi A1 - Kocher, Martin A1 - Sturm, Volker A1 - Maarouf, Mohammad T1 - Stereotactic LINAC-Radiosurgery for Glomus Jugulare Tumors: A Long-Term Follow-Up of 27 Patients JF - PLoS ONE N2 - Background The optimal treatment of glomus jugulare tumors (GJTs) remains controversial. Due to the critical location, microsurgery still provides high treatment-related morbidity and a decreased quality of life. Thus, we performed stereotactical radiosurgery (SRS) for the treatment of GJTs and evaluated the long-term outcome. Methods Between 1991 and 2011, 32 patients with GJTs underwent SRS using a linear accelerator (LINAC) either as primary or salvage therapy. Twenty-seven patients (median age 59.9 years, range 28.7-79.9 years) with a follow-up greater than five years (median 11 years, range 5.3-22.1 years) were selected for retrospective analysis. The median therapeutic single dose applied to the tumor surface was 15 Gy (range 11-20 Gy) and the median tumor volume was 9.5 ml (range 2.8-51 ml). Results Following LINAC-SRS, 10 of 27 patients showed a significant improvement of their previous neurological complaints, whereas 12 patients remained unchanged. Five patients died during follow-up due to old age or other, not treatment-related reasons. MR-imaging showed a partial remission in 12 and a stable disease in 15 patients. No tumor progression was observed. The actuarial overall survival rates after five, ten and 20 years were 100%, 95.2% and 79.4%, respectively. Conclusions Stereotactic LINAC-Radiosurgery can achieve an excellent long-term tumor control beside a low rate of morbidity in the treatment of GJTs. It should be considered as an alternative therapy regime to surgical resection or fractionated external beam radiation either as primary, adjuvant or salvage therapy. KW - gamma knife radiosurgery KW - accelerator based radiosurgery KW - radiation therapy KW - temporal bone KW - skull base KW - surgery KW - paragangliomas KW - management KW - radiotherapy KW - head Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151717 VL - 10 IS - 6 ER - TY - JOUR A1 - Maarouf, Mohammad A1 - Neudorfer, Clemens A1 - El Majdoub, Faycal A1 - Lenartz, Doris A1 - Kuhn, Jens A1 - Sturm, Volker T1 - Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series JF - PLoS ONE N2 - Background The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. Methods In this retrospective trial, four patients (three female, one male) aged 31–48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. Results Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed “partial response” on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. Conclusion MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders. KW - deep brain stimulation KW - obsessive-compulsive disorder Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166830 VL - 11 IS - 8 ER -