TY - JOUR A1 - Hartung, Andreas A1 - Seufert, Florian A1 - Berges, Carsten A1 - Gessner, Viktoria H. A1 - Holzgrabe, Ulrike T1 - One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties JF - Molecules N2 - The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic alpha-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with beta-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses. KW - multicomponent Ugi-type reaction KW - intramolecular Michael addition KW - strategy KW - derivates KW - diketopiperazines KW - chemistry KW - T cell KW - 2,5-diketopiperazines KW - anti-proliferative effects Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130423 VL - 17 IS - 12 ER - TY - THES A1 - Hartung, Andreas Walter T1 - Entwicklung neuartiger pharmakologischer Wirkstoffe als Inhibitoren des HSF-1/HSP70-Systems zur Behandlung des Multiplen Myeloms T1 - Development of novel pharmacological drugs as inhibitores of HSF-1/HSP70-System for the treatment of multiple myeloma N2 - Das Multiple Myelom (MM) zeichnet sich durch eine krankhafte Entartung der Plasmazellen im Knochenmark aus und gilt heute trotz zahlreicher Behandlungsfortschritte immer noch als unheilbar. Als attraktive Zielstrukturen für neue Therapiemöglichkeiten haben sich in den vergangenen Jahren „Heat-Shock“-Proteine etabliert. Diese liegen häufig überexprimiert vor und sind bei der Stabilisierung mehrerer onkogener Signalwege des MM von zentraler Bedeutung. Zunächst wurden von Pharmaunternehmen verschiedene Inhibitoren von HSP90 entwickelt, die sich in präklinischen MM-Studien als erfolgreich herausstellten, in klinischen Studien jedoch nur eine begrenzte Wirksamkeit zeigten, da eine Inhibition von HSP90 zu einer schnellen HSF-1-vermittelten Hochregulation der HSP70- Expression führt. Dies kompensiert die Inhibition von HSP90 und führt damit zu einer Abschwächung der Anti-Tumoraktivität. Eine duale Hemmung von HSP90 und des HSF-1/HSP70-Systems wird daher als vielversprechende Strategie für eine wirksame Behandlung des MM betrachtet. Die vorliegende Arbeit, die im Rahmen der klinischen Forschergruppe 216 erstellt wurde, befasst sich daher mit der Entwicklung von Inhibitoren des HSF-1/HSP70-Systems. Hierzu wurden zwei unabhängige Strategien verfolgt. Neben einem indirekten Ansatz, der auf einer blockierten HSP70-Expression via Inhibition des HSF-1-Signalwegs beruht, stand die direkte Inhibition von HSP70 im Fokus. Die erzielten Ergebnisse im Einzelnen: 1) In Anlehnung an den HSF-1-Inhibitor NZ28 (12) sollte untersucht werden, ob das dort enthaltene Tetrahydroisochinolin-Gerüst eine Leitstruktur für die Entwicklung von Hemmstoffen des HSF-1-Signalwegs darstellt. Hierzu wurde eine Reihe unterschiedlich substituierter Tetrahydroisochinolinon-Derivate hergestellt. Die Synthese erfolgte über eine sequenzielle Ugi-Heck-Reaktion, da hierbei drei Substituenten des Tetrahydro- isochinolin-Gerüsts hochflexibel und unabhängig voneinander variiert werden können und sich so leicht ein breites Spektrum verschiedener Tetrahydroisochinolinon-Derivate aufbauen lässt. Eine Bioaktivitätsanalyse zeigte jedoch, dass keine der so erhaltenen Verbindungen (26) die HSF-1-vermittelte HSP70-Expression zu inhibieren vermochte. Um den Einfluss des spezifischen Substitutionsmusters der via Ugi-Heck-Reaktion erhaltenen Produkte zu untersuchen, wurde außerdem eine Auswahl der als HSP70- Inhibitoren synthetisierten Tetrahydroisochinolinone (24 und 36) im HSF-1-Assay getestet. Da auch für diese Verbindungen keine Inhibition des Signalwegs beobachtet werden konnte, besteht Grund zur Annahme, dass substituierte Tetrahydroisochinolin-Derivate nicht als Leitstruktur für die Entwicklung von HSF-1-Inhibitoren geeignet sind. 2) Im Gegensatz zu den synthetisierten Tetrahydroisochinolinonen zeigten einige der als Zwischenprodukte der Ugi-Heck-Reaktion isolierten α-Acylaminocarboxamide, die durch ein Michael-System charakterisiert sind, eine Inhibition der HSF-1-vermittelten HSP70- Expression. Zwar konnten keine eindeutigen Struktur-Wirkungsbeziehungen bezüglich einzelner Substituenten abgeleitet werden, aber es zeigte sich, dass die beobachtete Bioaktivität nicht vom enthaltenen Michael-System abhängig ist. Dem Wirkprinzip der α-Acylaminocarboxamide scheint somit keine kovalente Bindung mit nukleophilen Seitenketten von Proteinen zugrunde zu liegen, was das Potenzial unspezifischer Interaktionen reduziert. 3) Bei der Ugi-Multikomponentenreaktion wurden als Carbonsäurederivate auch β-Acyl-substituierte Acrylsäuren eingesetzt. Dabei wurde beobachtet, dass dieser Austausch zur Bildung von pharmakologisch interessanten 2,5-Diketopiperazinderivaten (35) führt. Die in nur einem Reaktionsschritt erhaltenen 2,5-DKPs zeigten eine spezifische und dosisabhängige antiproliferative Wirkung auf aktivierte T-Zellen, was sie als potenzielle Wirkstoffkandidaten für die Behandlung von unbeabsichtigten T-Zell-vermittelten Autoimmunantworten interessant macht (AG Topp). Eine Analyse der Struktur-Wirkungsbeziehungen zeigte unter anderem eine Präferenz für trans-konfigurierte 2,5-DKPs. Die Aktivität der potentesten Verbindungen der syntheti- sierten Serie lag in derselben Größenordnung wie die der Positiv-Kontrolle 17-Dimethoxyaminoethylamino-17-demethoxygeldanamycin (17-DMAG, 4b). 4) Ausgangspunkt für die Entwicklung neuartiger HSP70-Inhibitoren war das Ergebnis eines virtuellen Screenings (AG Sotriffer), das darauf abzielte die Proteinfunktion durch eine Interaktion mit dem Interdomänen-Interface von HSP70 zu blockieren. Im ersten Schritt wurde eine diastereoselektive und hochflexible Reaktionssequenz zum virtuelle Screening-Hits (trans-24a) etabliert, mit der im zweiten Schritt eine Bibliothek verwandter Substanzen aufgebaut wurde. Gezielte strukturelle Modifikationen erlaubten dabei wesentliche Strukturelemente zu identifizieren sowie Informationen für die Generierung von Derivaten mit höherer Aktivität zu gewinnen. Die wichtigsten Erkenntnisse dabei waren: - Ausschließlich trans-konfigurierte Tetrahydroisochinolinon-Derivate sind wirksam. - Carboxamide (Pos. 4) sind aktiver als analoge Carbonsäuren. - Die Methoxyfunktion am Phenylsubstituenten in Pos.3 ist für die Aktivität wichtig, dagegen führt das Entfernen der OCH3- Gruppe am Phenylring in Pos. 2 zu einer Aktivitätssteigerung. - Eine aliphatische MeNH-Einheit am exozyklischen Amid reduziert die Aktivität gegenüber Arylamidsubstituenten um eine Zehnerpotenz. Darüber hinaus führt ein tertiärer Dimethylcarboxamid-Rest zum vollständigen Aktivitätsverlust. Zur Falsifizierung der postulierten Bindetasche wurden zusätzlich gezielt Derivate mit sterisch anspruchsvollen Substituenten (Tetrahydronaphthyl, Phenoxyphenyl) hergestellt, die nicht in der Lage sein sollten im berechneten Bindemodus am Interdomänen-Interface zu binden. Dabei stand das so ermittelte verfügbare Platzangebot in Einklang mit den aufgrund der Docking-Analysen getroffenen Annahmen. Um die Enantioselektivität der Aktivität der trans-Verbindungen zu prüfen, wurde für zwei repräsentative Carboxamide (24a und 24i) eine Enantiomerentrennung mittels chiraler HPLC durchgeführt und die Enantiomere einzeln getestet. Dabei erwiesen sich die R,R-Derivate als Träger der Anti-MM-Wirksamkeit. Zur Abschätzung der Permeabilität wurden die PSA-Werte der Carboxamide (24) berechnet. Mit Ausnahme der hydroxylsubstituierten Verbindung 24r lagen die Werte aller Derivate (24a-q) in einem Bereich von 65–88Å2, was einen akzeptablen Resorptionsanteil von 55–90% erwarten lässt. Die Bestimmung der Lipophilie der hergestellten Carboxamide mittels HPLC ergab einen logD-Bereich von 1–3, in dem Wirkstoffe einen ausgewogenen lipophilen Charakter besitzen. Die Effizienz der hergestellten Inhibitoren wurde darüber hinaus anhand der ermittelten LE- (engl. ligand efficiency) und LLE-Werte (engl. ligand lipophilic efficiency) beurteilt. Die günstigste Kombination aus LE und LLE wurde für Verbindung 24j (EC50 = 0.20 μM) ermittelt. Dieses Derivat zeichnet sich durch einen Phenylsubstituenten in Position2 des Tetrahydroisochinolin-Gerüsts, einen Methoxyphenylrest in Position3 und einen Pyrimidinsubstituenten am exozyklischen Amid aus. Zur Beurteilung unspezifisch toxischer Effekte wurde neben der Wirksamkeit an MM-Zellen auch der Einfluss der Tetrahydroisochinolin-Derivate auf die Viabilität von mononukleären Zellen des peripheren Blutes (PBMCs) untersucht (AG Chatterjee). Während die aktivsten Carboxamide an MM-Zellen im submikromolaren Bereich wirksam waren, zeigte mit Ausnahme des phenolsubstituierten Derivats trans-24r keine der getesteten Verbindungen toxische Effekte an PBMCs (EC50 > 100 μM). Darüber hinaus legen detaillierte Westernblot-Analysen einen HSP70-spezifischen Wirkmechanismus nahe. Außerdem führte eine duale Hemmung von HSP70 und HSP90 durch gleichzeitige Inkubation mit trans-24i und NVP-AUY922 (5) zu einem additiven pro-apoptotischen Effekt bei MM-Zellen. Aufgrund der vielversprechenden In-vitro-Ergebnisse und seiner guten Löslichkeit wurde trans-39c in vivo untersucht. Zu diesem Zweck wurden zunächst die physikochemischen Parameter pKa, logP und Löslichkeit sowie die Plasma-Proteinbindung ermittelt (in Kooperation mit AG Meinel). Auf Basis einer im Anschluss durchgeführten Pharmakokinetik-Simulation wurden zwei unterschiedliche Dosierungen gewählt. Toxizitätsuntersuchungen von trans-39c zeigten keine Hämolyseaktivität und keinen Effekt auf die Viabilität von Leber- und Nierenzellen (H. Bruhn). Für die In-vivo-Studie wurde ein murines MM-Modell verwendet, das auf MOPC-315.BM-Luciferase+-Zellen basiert und eine nicht-invasive In-vivo-Bestimmung der Tumorentwicklung via Biolumineszenz ermöglicht (AG Beilhack). Über einen Zeitraum von zehn Tagen wurde zwei Gruppen mit jeweils fünf Tieren behandelt. Dazu wurde trans-39c (4 bzw. 40 μg) im Abstand von 12 h intraperitoneal appliziert. Alle Versuchstiere tolerierten die Behandlung und die mit einer Dosis von 40 μg therapierte Gruppe zeigte eine signifikante Reduktion des Tumorwachstums gegenüber einer unbehandelten Kontrollgruppe. Dieses Ergebnis konnte zusätzlich durch eine im Anschluss durchgeführte Ex-vivo-Untersuchung bestätigt werden, bei der die Tumorlast in verschiedenen Knochen und Geweben ermittelt wurde. Die Tetrahydroisochinolinon-Derivate haben sich damit als ausgezeichnete Leitstruktur für die Weiterentwicklung als HSP70-Inhibitoren erwiesen und könnten in Zukunft zu einem deutlichen Fortschritt bei der Behandlung des Multiplen Myeloms beitragen. N2 - Multiple Myeloma (MM) is generally characterized by a malignant disorder of the plasma cells within the bone marrow. Despite some progress made in treatment, it still remains incurable. Since the past years heat shock proteins (HSPs) have been established as attractive targets for new therapies. HSPs are frequently overexpressed in MM and play an important role in stabilizing multiple oncogene signaling pathways. Initially pharmaceutical companies had developed various inhibitors of HSP90, which proved to be successful in preclinical MM studies. However, in clinical therapies they just showed limited potency since the inhibition of HSP90 leads to a strong and fast HSF-1-mediated upregulation of the HSP70 expression. This response is compensating the inhibition of HSP90 and leads to an attenuation of the antitumor activity. Therefore a dual depletion of HSP90 and the HSF- 1/HSP70 system is regarded as a promising strategy for an efficient treatment of MM. The present work, established within the Clinical Research Unit 216, deals with the development of inhibitors of the HSF-1/HSP70 system. Therefore two independent strategies were implemented, i.e. an inhibition of the HSF-1 signaling pathway and the direct inhibition of HSP70. The obtained results in detail: 1) According to the HSF-1 inhibitor NZ28 (12) it was tested whether its tetrahydro- isoquinoline-scaffold can serve as a lead structure for the development of HSF-1 pathway inhibitors. Hence a series of variously substituted tetrahydroisoquinolinone derivatives was prepared. The synthesis followed a sequential Ugi-Heck reaction, as this procedure offers the opportunity to vary three substituents of the tetrahydroisoquinoline-scaffold independently and highly flexible and therefore gives access to a library of different tetrahydroisoquinolinones. However, bioactivity analysis revealed that none of the obtained compounds (26) was able to inhibit the HSF-1-mediated HSP70 expression. In order to analyze the influence of the specific substitution pattern of the products from the Ugi-Heck reaction, a variety of the tetrahydroisoquinolinones (24 and 36) synthesized as inhibitors of HSP70 were additionally tested with the HSF-1 assay. As these compounds also showed no inhibition of the signaling pathway, it is supposed that substituted tetrahydroisoquinolines are no suitable lead structures for the development of HSF-1 inhibitors. 2) In contrast to the synthesized tetrahydroisoquinolinones, several α-acylaminocarbox- amides showed an inhibition of the HSF-1-mediated HSP70 expression. These compounds were obtained as intermediates of the Ugi-Heck reaction and are characterized through a Michael system. Although no distinct structure-activity relationship could be derived with regard to individual substituents, it could be shown that the observed bioactivity is independent from the Michael system included. Thus, the activity of the α-acylamino-carboxamides is apparently not restricted to a covalent bond formed along with nucleophilic protein side chains. This reduces the potential of unspecific interactions. 3) The Ugi reaction was also performed with β-acyl-substituted acrylic acids. Making use of such carbonic acids, access to pharmacological interesting 2,5-diketopiperazines (35) was gained in just one reaction step. The products obtained showed specific anti-proliferative properties towards activated T-cells in a dose-dependent manner. Therefore they represent potential candidates for treating unwanted T cell-mediated immune responses (explored in the group of Prof. Topp). Analyzing the structure-activity relationship revealed an explicit preference for trans-configured 2,5-DKPs. Moreover, the activity of the most potent compound was of the same magnitude as the positive control 17-dimethoxyaminoethylamino-17-demethoxygeldanamycin (17-DMAG, 4b) 4) For the development of novel HSP70 inhibitors it was aimed to prevent the protein function by an interaction with the interdomain interface of HSP70. A corresponding Virtual Screening (performed in the group of Prof. Sotriffer) yielded the tetrahydro- isoquinolinone trans-24a as most potent compound. Initially a diastereoselective and highly flexible reaction sequence to the virtual screening hit (trans-24a) was established which was then utilized to create a library of modified compounds. By means of systemic structural modifications significant moieties were identified and furthermore detailed information for creating derivatives with higher potency important results were: - Exclusively trans-configured tetrahydroisoquinolinones are highly active against MM cells. - Carboxamides (Pos. 4) are more potent than the corresponding carbonic acid and carboxylate analogues. - The methoxy function at the phenyl substituent in pos. 3 is important for the activity, whereas its absence at the phenyl ring in pos. 2 increases the potency. - An aliphatic MeNH-group at the exocyclic amide is reducing the activity against arylamide substituents by an order of magnitude. Moreover, a tertiary dimethylcarboxamide moiety causes the complete loss of activity. To falsify the postulated binding pocket, specific derivatives bearing structural challenging substituents (tetrahydronaphthyl, phenoxyphenyl) were synthetized additionally. They should not be able to bind to the interdomain interface in the calculated binding mode. As a result the available space was in good agreement with the assumptions made upon the docking analyses. In order to prove whether the activity of the trans-compounds is induced by only one enantiomer, two representative carboxamides (24a und 24i) were subjected to an enantioseparation by means of chiral HPLC. Exclusively the R,R-compounds were active. To estimate the compounds’ permeability, the PSA values of the carboxamides (24) were calculated. With exception of the hydroxyl substituted compound 24r, the values of all other derivatives (24a-q) ranged between 65–88 Å2. Thus, the fraction of absorption is expected to be 55–90%. The lipophilicity determined by means of HPLC yielded logD- values of 1–3, complying to a well-balanced lipophilic character. The efficiency of the synthesized inhibitors was evaluated by means of the calculated ligand efficiency (LE) and lipophilic ligand efficiency (LLE). The most favorable combination of LE and LLE was found for compound 24j (EC50 = 0.20 μM). It is characterized by a phenyl substituent in position 2 of the tetrahydroisoquinoline-scaffold, a methoxyphenyl group in position 3 and a pyrimidine substituent at the exocyclic amide. In addition to the analyzed potency against MM cells, the influence of the tetrahydroisoquinolines on peripheral blood mononuclear cells (PBMCs) was determined in order to appraise unspecific toxic effects (performed in the group of Dr. Chatterjee). While the most potent carboxamides showed activity against MM cells in a submicromolar concentration range, none of the tested compounds showed toxic effects against PBMCs (EC50 > 100 μM) with exception of the phenol substituted derivative trans-24r. Furthermore, detailed Westernblot analyses suggest a HSP70 specific mode of action. As expected the dual inhibition of HSP70 and HSP90 by means of concomitant incubation with trans-24i and NVP-AUY922 (5) yielded an additive pro-apoptotic effect against MM cells. Based on these promising in vitro results compound trans-39c was subjected to an in vivo study. For this purpose the physicochemical parameters pKa, logP and solubility were determined initially (in collaboration with the group of Prof. Meinel) as well as the degree of plasma protein binding. Pharmacokinetic simulations were the fundamental for the two different dosages selected afterwards. In order to evaluate the potential of toxicity in more detail, the compounds’ hemolysis activity and its impact on the viability of liver and kidney cells were determined by H. Bruhn. These analyses did not reveal any cytotoxic effect. The in vivo study was performed with a novel murine MM model that based on MOPC-315.BM luciferase+ cells and therefore allows the none-invasive determination of tumor growth by means of bioluminescence imaging (developed and performed in the group of Prof. Beilhack). Two groups of five animals each were treated over a period of ten days. Therefore trans-39c (4 and 40μg, respectively) was injected intraperitoneal every 12 h. The therapy was well tolerated by all animals and the group treated with the higher dose of 40μg showed a significant reduction of tumor growth compared to the untreated control group. This result could be supplemented by ex vivo analyses performed subsequently where the tumor burden in different bones and tissues was determined. Ultimately the tetrahydroisoquinolinones have been established as excellent lead structures for an advanced development as HSP70 inhibitors and may contribute to a considerable progress in treatment of Multiple Myeloma in the future. KW - Plasmozytom KW - Hitzeschock Proteine KW - Hitzeschock-Proteine KW - Hitzeschocktranskriptionsfaktor KW - Multiples Myelom KW - HSF-1 KW - HSP70 KW - therapeutisches Target KW - Heatshock Proteins KW - Multiple Myeloma KW - therapeutic strategy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-91390 ER - TY - JOUR A1 - Esser, Peter A1 - Mehnert‐Theuerkauf, Anja A1 - Friedrich, Michael A1 - Johansen, Christoffer A1 - Brähler, Elmar A1 - Faller, Hermann A1 - Härter, Martin A1 - Koch, Uwe A1 - Schulz, Holger A1 - Wegscheider, Karl A1 - Weis, Joachim A1 - Kuba, Katharina A1 - Hinz, Andreas A1 - Hartung, Tim T1 - Risk and associated factors of depression and anxiety in men with prostate cancer: Results from a German multicenter study JF - Psycho‐Oncology N2 - Objective In order to optimize psycho‐oncological care, studies that quantify the extent of distress and identify certain risk groups are needed. Among patients with prostate cancer (PCa), findings on depression and anxiety are limited. Methods We analyzed data of PCa patients selected from a German multi‐center study. Depression and anxiety were assessed with the PHQ‐9 and the GAD‐7 (cut‐off ≥7). We provided physical symptom burden, calculated absolute and relative risk (AR and RR) of depression and anxiety across patient subsets and between patients and the general population (GP) and tested age as a moderator within the relationship of disease‐specific symptoms with depression and anxiety. Results Among 636 participants, the majority reported disease‐specific problems (sexuality: 60%; urination: 52%). AR for depression and anxiety was 23% and 22%, respectively. Significant RR were small, with higher risks of distress in patients who are younger (eg, RR\(_{depression}\) = 1.15; 95%‐CI: 1.06‐1.26), treated with chemotherapy (RR\(_{depression}\)n = 1.46; 95%‐CI: 1.09‐1.96) or having metastases (RR\(_{depression}\) = 1.30; 95%‐CI: 1.02‐1.65). Risk of distress was slightly elevated compared to GP (eg, RR\(_{depression}\) = 1.13; 95%‐CI: 1.07‐1.19). Age moderated the relationship between symptoms and anxiety (B\(_{urination}\) = −0.10, P = .02; B\(_{sexuality}\) = −0.11, P = .01). Conclusions Younger patients, those with metastases or treatment with chemotherapy seem to be at elevated risk for distress and should be closely monitored. Many patients suffer from disease‐specific symptom burden, by which younger patients seem to be particularly distressed. Support of coping mechanisms associated with disease‐specific symptom burden seems warranted. KW - anxiety KW - cancer KW - depression KW - oncology KW - prostatic neoplasms Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218277 VL - 29 IS - 10 SP - 1604 EP - 1612 ER - TY - JOUR A1 - Gruschwitz, Philipp A1 - Hartung, Viktor A1 - Kleefeldt, Florian A1 - Ergün, Süleyman A1 - Lichthardt, Sven A1 - Huflage, Henner A1 - Hendel, Robin A1 - Kunz, Andreas Steven A1 - Pannenbecker, Pauline A1 - Kuhl, Philipp Josef A1 - Augustin, Anne Marie A1 - Bley, Thorsten Alexander A1 - Petritsch, Bernhard A1 - Grunz, Jan-Peter T1 - Standardized assessment of vascular reconstruction kernels in photon-counting CT angiographies of the leg using a continuous extracorporeal perfusion model JF - Scientific Reports N2 - This study evaluated the influence of different vascular reconstruction kernels on the image quality of CT angiographies of the lower extremity runoff using a 1st-generation photon-counting-detector CT (PCD-CT) compared with dose-matched examinations on a 3rd-generation energy-integrating-detector CT (EID-CT). Inducing continuous extracorporeal perfusion in a human cadaveric model, we performed CT angiographies of eight upper leg arterial runoffs with radiation dose-equivalent 120 kVp acquisition protocols (CTDIvol 5 mGy). Reconstructions were executed with different vascular kernels, matching the individual modulation transfer functions between scanners. Signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were computed to assess objective image quality. Six radiologists evaluated image quality subjectively using a forced-choice pairwise comparison tool. Interrater agreement was determined by calculating Kendall’s concordance coefficient (W). The intraluminal attenuation of PCD-CT images was significantly higher than of EID-CT (414.7 ± 27.3 HU vs. 329.3 ± 24.5 HU; p < 0.001). Using comparable kernels, image noise with PCD-CT was significantly lower than with EID-CT (p ≤ 0.044). Correspondingly, SNR and CNR were approximately twofold higher for PCD-CT (p < 0.001). Increasing the spatial frequency for PCD-CT reconstructions by one level resulted in similar metrics compared to EID-CT (CNRfat; EID-CT Bv49: 21.7 ± 3.7 versus PCD-CT Bv60: 21.4 ± 3.5). Overall image quality of PCD-CTA achieved ratings superior to EID-CTA irrespective of the used reconstruction kernels (best: PCD-CT Bv60; worst: EID-CT Bv40; p < 0.001). Interrater agreement was good (W = 0.78). Concluding, PCD-CT offers superior intraluminal attenuation, SNR, and CNR compared to EID-CT in angiographies of the upper leg arterial runoff. Combined with improved subjective image quality, PCD-CT facilitates the use of sharper convolution kernels and ultimately bears the potential of improved vascular structure assessability. KW - experimental models of disease KW - preclinical research KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357912 VL - 13 ER - TY - JOUR A1 - Gruschwitz, Philipp A1 - Hartung, Viktor A1 - Ergün, Süleyman A1 - Peter, Dominik A1 - Lichthardt, Sven A1 - Huflage, Henner A1 - Hendel, Robin A1 - Pannenbecker, Pauline A1 - Augustin, Anne Marie A1 - Kunz, Andreas Steven A1 - Feldle, Philipp A1 - Bley, Thorsten Alexander A1 - Grunz, Jan-Peter T1 - Comparison of ultrahigh and standard resolution photon-counting CT angiography of the femoral arteries in a continuously perfused in vitro model JF - European Radiology Experimental N2 - Background With the emergence of photon-counting CT, ultrahigh-resolution (UHR) imaging can be performed without dose penalty. This study aims to directly compare the image quality of UHR and standard resolution (SR) scan mode in femoral artery angiographies. Methods After establishing continuous extracorporeal perfusion in four fresh-frozen cadaveric specimens, photon-counting CT angiographies were performed with a radiation dose of 5 mGy and tube voltage of 120 kV in both SR and UHR mode. Images were reconstructed with dedicated convolution kernels (soft: Body-vascular (Bv)48; sharp: Bv60; ultrasharp: Bv76). Six radiologists evaluated the image quality by means of a pairwise forced-choice comparison tool. Kendall’s concordance coefficient (W) was calculated to quantify interrater agreement. Image quality was further assessed by measuring intraluminal attenuation and image noise as well as by calculating signal-to-noise ratio (SNR) and contrast-to-noise ratios (CNR). Results UHR yielded lower noise than SR for identical reconstructions with kernels ≥ Bv60 (p < 0.001). UHR scans exhibited lower intraluminal attenuation compared to SR (Bv60: 406.4 ± 25.1 versus 418.1 ± 30.1 HU; p < 0.001). Irrespective of scan mode, SNR and CNR decreased while noise increased with sharper kernels but UHR scans were objectively superior to SR nonetheless (Bv60: SNR 25.9 ± 6.4 versus 20.9 ± 5.3; CNR 22.7 ± 5.8 versus 18.4 ± 4.8; p < 0.001). Notably, UHR scans were preferred in subjective assessment when images were reconstructed with the ultrasharp Bv76 kernel, whereas SR was rated superior for Bv60. Interrater agreement was high (W = 0.935). Conclusions Combinations of UHR scan mode and ultrasharp convolution kernel are able to exploit the full image quality potential in photon-counting CT angiography of the femoral arteries. Relevance statement The UHR scan mode offers improved image quality and may increase diagnostic accuracy in CT angiography of the peripheral arterial runoff when optimized reconstruction parameters are chosen. Key points • UHR photon-counting CT improves image quality in combination with ultrasharp convolution kernels. • UHR datasets display lower image noise compared with identically reconstructed standard resolution scans. • Scans in UHR mode show decreased intraluminal attenuation compared with standard resolution imaging. KW - CT angiography KW - femoral arteries KW - photon-counting computed tomography (CT) KW - small pixel effect KW - ultrahigh resolution Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357905 VL - 7 ER - TY - JOUR A1 - Luetkens, Karsten Sebastian A1 - Grunz, Jan-Peter A1 - Kunz, Andreas Steven A1 - Huflage, Henner A1 - Weißenberger, Manuel A1 - Hartung, Viktor A1 - Patzer, Theresa Sophie A1 - Gruschwitz, Philipp A1 - Ergün, Süleyman A1 - Bley, Thorsten Alexander A1 - Feldle, Philipp T1 - Ultra-high-resolution photon-counting detector CT arthrography of the ankle: a feasibility study JF - Diagnostics N2 - This study was designed to investigate the image quality of ultra-high-resolution ankle arthrography employing a photon-counting detector CT. Bilateral arthrograms were acquired in four cadaveric specimens with full-dose (10 mGy) and low-dose (3 mGy) scan protocols. Three convolution kernels with different spatial frequencies were utilized for image reconstruction (ρ\(_{50}\); Br98: 39.0, Br84: 22.6, Br76: 16.5 lp/cm). Seven radiologists subjectively assessed the image quality regarding the depiction of bone, hyaline cartilage, and ligaments. An additional quantitative assessment comprised the measurement of noise and the computation of contrast-to-noise ratios (CNR). While an optimal depiction of bone tissue was achieved with the ultra-sharp Br98 kernel (S ≤ 0.043), the visualization of cartilage improved with lower modulation transfer functions at each dose level (p ≤ 0.014). The interrater reliability ranged from good to excellent for all assessed tissues (intraclass correlation coefficient ≥ 0.805). The noise levels in subcutaneous fat decreased with reduced spatial frequency (p < 0.001). Notably, the low-dose Br76 matched the CNR of the full-dose Br84 (p 0.999) and superseded Br98 (p < 0.001) in all tissues. Based on the reported results, a photon-counting detector CT arthrography of the ankle with an ultra-high-resolution collimation offers stellar image quality and tissue assessability, improving the evaluation of miniscule anatomical structures. While bone depiction was superior in combination with an ultra-sharp convolution kernel, soft tissue evaluation benefited from employing a lower spatial frequency. KW - photon-counting CT KW - arthrography KW - ankle KW - cartilage KW - radiation dosage Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362622 SN - 2075-4418 VL - 13 IS - 13 ER -