TY - JOUR A1 - Moustafa, Moataz A. M. A1 - Fouad, Eman A. A1 - Ibrahim, Emad A1 - Erdei, Anna Laura A1 - Kárpáti, Zsolt A1 - Fónagy, Adrien T1 - The comparative toxicity, biochemical and physiological impacts of chlorantraniliprole and indoxacarb on Mamestra brassicae (Lepidoptera: Noctuidae) JF - Toxics N2 - Background: The cabbage moth, Mamestra brassicae, is a polyphagous pest that attacks several crops. Here, the sublethal and lethal effects of chlorantraniliprole and indoxacarb were investigated on the developmental stages, detoxification enzymes, reproductive activity, calling behavior, peripheral physiology, and pheromone titer of M. brasssicae. Methods: To assess pesticide effects, the second instar larvae were maintained for 24 h on a semi-artificial diet containing insecticides at their LC\(_{10}\), LC\(_{30}\), and LC\(_{50}\) concentrations. Results: M. brassicae was more susceptible to chlorantraniliprole (LC\(_{50}\) = 0.35 mg/L) than indoxacarb (LC\(_{50}\) = 1.71 mg/L). A significantly increased developmental time was observed with both insecticides at all tested concentrations but decreases in pupation rate, pupal weight, and emergence were limited to the LC50 concentration. Reductions in both the total number of eggs laid per female and the egg viability were observed with both insecticides at their LC\(_{30}\) and LC\(_{50}\) concentrations. Both female calling activity and the sex pheromone (Z11-hexadecenyl acetate and hexadecenyl acetate) titer were significantly reduced by chlorantraniliprole in LC\(_{50}\) concentration. Antennal responses of female antennae to benzaldehyde and 3-octanone were significantly weaker than controls after exposure to the indoxocarb LC\(_{50}\) concentration. Significant reductions in the enzymatic activity of glutathione S-transferases, mixed-function oxidases, and carboxylesterases were observed in response to both insecticides. KW - toxicity KW - sublethal effects KW - chlorantraniliprole KW - indoxacarb KW - Mamestra brassicae Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303931 SN - 2305-6304 VL - 11 IS - 3 ER - TY - JOUR A1 - Koch, Elias A. T. A1 - Petzold, Anne A1 - Wessely, Anja A1 - Dippel, Edgar A1 - Gesierich, Anja A1 - Gutzmer, Ralf A1 - Hassel, Jessica C. A1 - Haferkamp, Sebastian A1 - Kähler, Katharina C. A1 - Knorr, Harald A1 - Kreuzberg, Nicole A1 - Leiter, Ulrike A1 - Loquai, Carmen A1 - Meier, Friedegund A1 - Meissner, Markus A1 - Mohr, Peter A1 - Pföhler, Claudia A1 - Rahimi, Farnaz A1 - Schadendorf, Dirk A1 - Schell, Beatrice A1 - Schlaak, Max A1 - Terheyden, Patrick A1 - Thoms, Kai-Martin A1 - Schuler-Thurner, Beatrice A1 - Ugurel, Selma A1 - Ulrich, Jens A1 - Utikal, Jochen A1 - Weichenthal, Michael A1 - Ziller, Fabian A1 - Berking, Carola A1 - Heppt, Markus V. T1 - Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity JF - Cancers N2 - Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities. KW - uveal melanoma KW - immune checkpoint blockade KW - PD-1 KW - CTLA-4 KW - re-induction KW - treatment resistance KW - toxicity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254814 SN - 2072-6694 VL - 14 IS - 3 ER - TY - THES A1 - Bertelsmann, Dietmar T1 - Analysis of the Frequency of Kidney Toxicity in Preclinical Safety Studies using the eTOX Database T1 - Analyse der Häufigkeit von Nierentoxizität in präklinischen Sicherheitsstudien unter Verwendung der eTOX-Datenbank N2 - This research aimed to obtain reliable data on the frequency of different types of renal toxicity findings in 28-day oral gavage studies in Wistar rats, their consistency across species and study duration, as well as the correlation between histopathological endpoints and routinely used clinical chemistry parameters indicative of kidney injury. Analysis of renal histopathological findings was carried out through extraction of information from the IMI eTOX database. Spontaneous renal histopathological findings in 28-day oral gavage studies in control Wistar rats and beagle dogs confirmed tubular basophilia and renal dilation as the most frequent incidental findings in controls, whereas necrosis and glomerulosclerosis were not identified at all or only rarely as a background lesion. Histopathological evidence of necrosis and glomerulosclerosis was associated with changes in clinical chemistry parameters in 28-day oral gavage Wistar rat studies. Necrosis was frequently accompanied by a statistically significant rise in serum creatinine and serum urea, whereas serum albumin was frequently found to decrease statistically significantly in treatment groups in which necrosis was recorded. In contrast to necrosis, glomerulosclerosis was not associated with statistically significant changes in serum creatinine and urea in any of the 28-day oral gavage Wistar rat treatment groups, but appears to be best reflected by a pattern of statistically significantly lowered serum albumin and serum protein together with a statistically significant increase in serum cholesterol. As might have been expected based on the high background incidences of tubular basophilia and dilation, no consistent changes in any of the clinical chemistry parameters were evident in animals in which renal lesions were con� fined to renal tubular basophilia or dilation. In summary, the routinely provided clinical chemistry parameters are rather insensitive - novel kidney biomarkers such as Cystatin C, β-trace protein and Kidney injury molecule 1 should further be evaluated and integrated into routine preclinical and clinical practice. However, evaluation of clinical chemistry data was limited by the lack of individual animal data. Even though an extensive amount of preclinical studies is accessible through the eTOX database, comparison of consistency across time was limited by the limited number of shorter- and longer term studies conducted with the compounds identified as causing renal histopathological changes within a 28- day study in rats. A high consistency across time for both treatment-related tubular basophilia and treatment-related dilation cannot be confirmed for either of the two effects as these two findings were both induced only rarely in studies over a different treatment-duration other than 28 days after administration of the compounds which provoked the respective effect in a 28-day study. For the finding of necrosis consistency across time was low with the exception of “AZ_GGA_200002321”, in which renal papillary necrosis was identified consist� ently throughout different treatment durations (2, 4, 26, 104 weeks). No shorter and longer-term studies were available for the compounds identified as causing glomerulosclerosis within a 28-day study in rats. No consistent findings of the selected histopathological endpoints were identified in any of the corresponding 28-day oral gavage beagle dog studies after treatment with the identical compounds, which caused the respective ef� fect after 28-day treatment in rats. However, in the overwhelming majority of cases, beagle dogs were administered lower doses in these studies in compar� ison to the corresponding 28-day Wistar rat studies. Searching the eTOX database yielded no 28-day oral gavage studies in Wistar and Wistar Han rats in which accumulation of hyaline droplets, tubular atrophy or hyperplasia was recorded. Only one 28-day oral gavage Wistar rat study was identified with the histopathological result of neutrophilic inflammation. Consequently, evaluation of these four renal findings in relation to clinical chemistry parameters and consistency across time and species cannot be made. In summary, this work contributes knowledge through mining and evaluating the eTOX database on a variety of specific renal endpoints that frequently occur after administration of trial substances in 28-day oral gavage studies in Wistar rats in the field of preclinical toxicity with specific focus on their frequency relation to background findings, as well as consistency across time and species. Targeted statistical evaluation of in vivo data within joint research ventures such as the eTOX project, presents an enormous opportunity for an innovative future way of aiding preclinical research towards a more efficient research in the preclinical stage of drug development. This could be achieved through the aug� mentation of methodological strategies and possibly novel software tools in order to predict in vivo toxicology of new molecular entities by means of information that is already available before early stages of the drug development pipeline begin. N2 - Diese Arbeit zielte darauf ab, verlässliche Daten über die Häufigkeit verschiedener Arten von Nierentoxizitätsbefunden in 28-tägigen oralen Sondenstudien an Wistar-Ratten zu erhalten. Untersucht wurde weiterhin die Konsistenz der Toxizitätsbefunde unterschiedlicher Spezies und Studiendauer sowie die Korrelation zwischen histopathologischen Endpunkten und routinemäßig verwendeten klinisch-chemischen Parametern, die auf eine Nierenschädigung hinweisen. Die Analyse der histopathologischen Nierenbefunde wurde durch Extraktion von Informationen aus der IMI eTOX-Datenbank durchgeführt. Spontane renale histopathologische Befunde in 28-tägigen oralen Sondenstudien an Wistar-Ratten und Beagles bestätigten tubuläre Basophilie und renale Dilatation als häufigste Nebenbefunde bei den Kontrolltieren, während Nekrose und Glomerulosklerose gar nicht oder nur selten als Hintergrundläsion identifiziert wurden. Der histopathologische Nachweis von Nekrose und Glomerulosklerose war mit Änderungen der klinisch-chemischen Parameter in 28-tägigen Wistar-Rattenstudien mit oraler Sonde verbunden. Nekrose ging häufig mit einem statistisch signifikanten Anstieg von Serumkreatinin und Serumharnstoff einher, während Serumalbumin in Behandlungsgruppen, in denen Nekrose aufgezeichnet wurde, häufig statistisch signifikant abnahm. Im Gegensatz zur Nekrose war Glomerulosklerose in keiner der 28-tägigen Wistar-Ratten-Behandlungsgruppen mit oraler Sonde mit statistisch signifikanten Veränderungen von Serumkreatinin und Harnstoff assoziiert, sondern scheint sich am besten in einem Muster von statistisch signifikant erniedrigtem Serumalbumin und Serumprotein zusammen mit einem statistisch signifikanten Anstieg des Serumcholesterins widerzuspiegeln. Wie aufgrund der hohen Hintergrundinzidenzen von tubulärer Basophilie und Dilatation zu erwarten war, waren bei Tieren, bei denen Nierenläsionen auf renale tubuläre Basophilie oder Dilatation beschränkt waren, keine konsistenten Änderungen der klinisch-chemischen Parameter erkennbar. Zusammenfassend sind die routinemäßig bereitgestellten klinisch-chemischen Parameter eher unempfindlich - neuartige Nieren-Biomarker wie „Cystatin C“, „β-trace protein“ und „Kidney injury molecule 1“ sollten weiter evaluiert und in die routinemäßige präklinische und klinische Praxis integriert werden. Die Auswertung der Daten zur klinischen Chemie war jedoch durch das Fehlen individueller Tierdaten begrenzt. Trotz der umfangreichen Anzahl an präklinischen Studien in der eTOX-Datenbank wurde der zeitliche Vergleich der Konsistenz durch die begrenzte Anzahl von Kurz- und Langzeitstudien eingeschränkt, welche mit denselben Substanzen durchgeführt wurden, die innerhalb einer 28-Tage-Studie an Ratten als Verursacher von renalen histopathologischen Veränderungen identifiziert wurden. Eine hohe zeitliche Konsistenz sowohl für die behandlungsbedingte tubuläre Basophilie und Dilatation kann für keinen der beiden Effekte bestätigt werden, da diese beiden Befunde nur selten in Studien über eine andere Behandlungsdauer als 28 Tage nach Verabreichung derselben Substanzen, die den jeweiligen Effekt in einer 28-Tage-Studie hervorriefen, induziert wurden. Für den Befund der Nekrose war die zeitliche Konsistenz gering. Eine Ausnahme stellte Substanz "AZ_GGA_200002321" dar, bei der über verschiedene Behandlungsdauern (2, 4, 26, 104 Wochen) hinweg konstant renale papilläre Nekrose festgestellt wurde. Für die Substanzen, die in einer 28-Tage-Studie an Ratten als glomeruloskleroseauslösend identifiziert wurden, waren keine Kurz- und Langzeitstudien verfügbar. In keiner der korrespondierenden 28-Tage-Studien an Beagles mit oraler Sonde wurden konsistente Befunde der ausgewählten histopathologischen Endpunkte nach Behandlung mit den identischen Verbindungen, die den jeweiligen Effekt nach 28-tägiger Behandlung in Ratten verursachten, festgestellt. In der überwiegenden Mehrheit der Fälle wurden den Beagles in diesen Studien im Vergleich zu den entsprechenden 28-Tage-Wistar-Rattenstudien niedrigere Dosen verabreicht. In der eTOX-Datenbank konnten keine 28-tägigen oralen Sondenstudien an Wistar- und Wistar-Han-Ratten gefunden werden, in denen eine Akkumulation von hyalinen Tröpfchen, tubuläre Atrophie oder Hyperplasie aufgezeichet wurde. Nur eine 28-tägige Wistar-Rattenstudie wurde mit dem histopathologischen Ergebnis einer neutrophilen Entzündung identifiziert. Folglich kann eine Bewertung dieser vier Nierenbefunde in Bezug auf klinische Chemie und Konsistenz über Zeit und Spezies nicht vorgenommen werden. Insgesamt zeigt dieser Arbeit, dass eine gezielte statistische Auswertung von in vivo-Daten im Rahmen von Forschungsverbünden wie dem eTOX-Projekt eine enorme Chance bietet, die präklinische Forschung in Zukunft auf dem Weg zu einer effizienteren Forschung in der präklinischen Phase der Arzneimittelentwicklung zu unterstützen. Dies könnte außerdem durch die Erweiterung methodischer Strategien und möglicherweise neuartiger Software-Tools erreicht werden, um die In-vivo-Toxikologie neuer molekularer Entitäten mit Hilfe von Informationen vorherzusagen, die bereits vor Beginn der Arzneimittelentwicklungspipeline verfügbar sind. KW - renal toxicity KW - etox database KW - rats KW - toxicity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257104 ER - TY - JOUR A1 - Diefenhardt, Markus A1 - Martin, Daniel A1 - Ludmir, Ethan B. A1 - Fleischmann, Maximilian A1 - Hofheinz, Ralf-Dieter A1 - Ghadimi, Michael A1 - Kosmala, Rebekka A1 - Polat, Bülent A1 - Friede, Tim A1 - Minsky, Bruce D. A1 - Rödel, Claus A1 - Fokas, Emmanouil T1 - Development and validation of a predictive model for toxicity of neoadjuvant chemoradiotherapy in rectal cancer in the CAO/ARO/AIO-04 phase III trial JF - Cancers N2 - Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making. KW - rectal cancer KW - toxicity KW - neoadjuvant KW - chemoradiotherapy KW - risk score Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288081 SN - 2072-6694 VL - 14 IS - 18 ER - TY - JOUR A1 - Tamihardja, Jörg A1 - Lawrenz, Ingulf A1 - Lutyj, Paul A1 - Weick, Stefan A1 - Guckenberger, Matthias A1 - Polat, Bülent A1 - Flentje, Michael T1 - Propensity score-matched analysis comparing dose-escalated intensity-modulated radiation therapy versus external beam radiation therapy plus high-dose-rate brachytherapy for localized prostate cancer JF - Strahlentherapie und Onkologie N2 - Purpose Dose-escalated external beam radiation therapy (EBRT) and EBRT + high-dose-rate brachytherapy (HDR-BT) boost are guideline-recommended treatment options for localized prostate cancer. The purpose of this study was to compare long-term outcome and toxicity of dose-escalated EBRT versus EBRT + HDR-BT boost. Methods From 2002 to 2019, 744 consecutive patients received either EBRT or EBRT + HDR-BT boost, of whom 516 patients were propensity score matched. Median follow-up was 95.3 months. Cone beam CT image-guided EBRT consisted of 33 fractions of intensity-modulated radiation therapy with simultaneous integrated boost up to 76.23 Gy (D\(_{Mean}\)). Combined treatment was delivered as 46 Gy (D\(_{Mean}\)) EBRT, followed by two fractions HDR-BT boost with 9 Gy (D\(_{90\%}\)). Propensity score matching was applied before analysis of the primary endpoint, estimated 10-year biochemical relapse-free survival (bRFS), and the secondary endpoints metastasis-free survival (MFS) and overall survival (OS). Prognostic parameters were analyzed by Cox proportional hazard modelling. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation used the Common Toxicity Criteria for Adverse Events (v5.0). Results The estimated 10-year bRFS was 82.0% vs. 76.4% (p = 0.075) for EBRT alone versus combined treatment, respectively. The estimated 10-year MFS was 82.9% vs. 87.0% (p = 0.195) and the 10-year OS was 65.7% vs. 68.9% (p = 0.303), respectively. Cumulative 5‑year late GU ≥ grade 2 toxicities were seen in 23.6% vs. 19.2% (p = 0.086) and 5‑year late GI ≥ grade 2 toxicities in 11.1% vs. 5.0% of the patients (p = 0.002); cumulative 5‑year late grade 3 GU toxicity occurred in 4.2% vs. 3.6% (p = 0.401) and GI toxicity in 1.0% vs. 0.3% (p = 0.249), respectively. Conclusion Both treatment groups showed excellent long-term outcomes with low rates of severe toxicity. KW - long-term outcome KW - dose escalation KW - high-dose-rate brachytherapy boost KW - propensity score matching KW - toxicity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325055 VL - 198 IS - 8 ER - TY - JOUR A1 - Tamihardja, Jörg A1 - Lutyj, Paul A1 - Kraft, Johannes A1 - Lisowski, Dominik A1 - Weick, Stefan A1 - Flentje, Michael A1 - Polat, Bülent T1 - Two-Weekly High-Dose-Rate Brachytherapy Boost After External Beam Radiotherapy for Localized Prostate Cancer: Long-Term Outcome and Toxicity Analysis JF - Frontiers in Oncology N2 - Purpose Evaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer. Methods 338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition. Results Median follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%. Conclusions Two-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control. KW - prostate cancer KW - high-dose-rate (HDR) brachytherapy KW - radiotherapy KW - long-term outcome KW - toxicity KW - external beam radiotherapy (EBRT) KW - biochemical relapse free survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250992 SN - 2234-943X VL - 11 ER - TY - JOUR A1 - Radeloff, Katrin A1 - Ramos Tirado, Mario A1 - Haddad, Daniel A1 - Breuer, Kathrin A1 - Müller, Jana A1 - Hochmuth, Sabine A1 - Hackenberg, Stephan A1 - Scherzad, Agmal A1 - Kleinsasser, Norbert A1 - Radeloff, Andreas T1 - Superparamagnetic iron oxide particles (VSOPs) show genotoxic effects but no functional impact on human adipose tissue-derived stromal cells (ASCs) JF - Materials N2 - Adipose tissue-derived stromal cells (ASCs) represent a capable source for cell-based therapeutic approaches. For monitoring a cell-based application in vivo, magnetic resonance imaging (MRI) of cells labeled with iron oxide particles is a common method. It is the aim of the present study to analyze potential DNA damage, cytotoxicity and impairment of functional properties of human (h)ASCs after labeling with citrate-coated very small superparamagnetic iron oxide particles (VSOPs). Cytotoxic as well as genotoxic effects of the labeling procedure were measured in labeled and unlabeled hASCs using the MTT assay, comet assay and chromosomal aberration test. Trilineage differentiation was performed to evaluate an impairment of the differentiation potential due to the particles. Proliferation as well as migration capability were analyzed after the labeling procedure. Furthermore, the labeling of the hASCs was confirmed by Prussian blue staining, transmission electron microscopy (TEM) and high-resolution MRI. Below the concentration of 0.6 mM, which was used for the procedure, no evidence of genotoxic effects was found. At 0.6 mM, 1 mM as well as 1.5 mM, an increase in the number of chromosomal aberrations was determined. Cytotoxic effects were not observed at any concentration. Proliferation, migration capability and differentiation potential were also not affected by the procedure. Labeling with VSOPs is a useful labeling method for hASCs that does not affect their proliferation, migration and differentiation potential. Despite the absence of cytotoxicity, however, indications of genotoxic effects have been demonstrated. KW - ASCs KW - adipose tissue-derived stromal cells KW - VSOP KW - iron oxide nanoparticles KW - toxicity KW - MRI KW - cell labeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222970 SN - 1996-1944 VL - 14 IS - 2 ER - TY - JOUR A1 - Isberner, Nora A1 - Kraus, Sabrina A1 - Grigoleit, Götz Ulrich A1 - Aghai, Fatemeh A1 - Kurlbaum, Max A1 - Zimmermann, Sebastian A1 - Klinker, Hartwig A1 - Scherf-Clavel, Oliver T1 - Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial JF - Cancer Chemotherapy and Pharmacology N2 - Purpose Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. Methods 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. Results Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). Conclusion Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity. KW - toxicity KW - Ruxolitinib KW - graft versus host disease KW - therapeutic drug monitoring KW - CYP3A4 KW - CYP2C9 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266476 SN - 1432-0843 VL - 88 IS - 6 ER - TY - JOUR A1 - Topp, Max S. A1 - van Meerten, Tom A1 - Houot, Roch A1 - Minnema, Monique C. A1 - Bouabdallah, Krimo A1 - Lugtenburg, Pieternella J. A1 - Thieblemont, Catherine A1 - Wermke, Martin A1 - Song, Kevin W. A1 - Avivi, Irit A1 - Kuruvilla, John A1 - Dührsen, Ulrich A1 - Zheng, Yan A1 - Vardhanabhuti, Saran A1 - Dong, Jinghui A1 - Bot, Adrian A1 - Rossi, John M. A1 - Plaks, Vicki A1 - Sherman, Marika A1 - Kim, Jenny J. A1 - Kerber, Anne A1 - Kersten, Marie José T1 - Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma JF - British Journal of Haematology N2 - Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel–related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel. KW - toxicity KW - large B-cell lymphoma KW - axi-cel KW - CAR T KW - corticosteroids Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258342 VL - 195 IS - 3 ER - TY - THES A1 - Kircher, Malte Tim T1 - Neuronale Genotoxizität von Angiotensin II T1 - Neuronal Genotoxicity of Angiotensin II N2 - In recent decades, the acceptance has steadily increased that oxidative stress plays an important role in the development of chronic diseases, malignant neoplasia and the acceleration of the aging process. As one of the most common chronic diseases, hypertension is often associated with a misregulated renin-angiotensin-aldosterone system that causes chronic oxidative stress. Hypertension is a risk factor for neurological diseases such as vascular dementia (VaD) and many neurological disorders, including VaD, have an ROS-associated or inflammatory component in their etiology. Our group has already demonstrated AT-II-induced genotoxicity in kidney and myocardial cells and tissues. The aim of this dissertation was to investigate a possible association between AT-II and neurodegeneration that is triggered by neuronal genotoxicity of AT-II. First, we showed in two neuronal cell lines that AT-II causes dose-dependent genome damage. Subsequent experiments could attribute this toxicity to NOX-produced superoxide generated after AT-II binding to the AT1R. In addition, AT-II-induced depletion of the most important intracellular antioxidant - glutathione - was demonstrated. In vivo, we were able to show that AT1aR knockout mice after AT-II treatment showed significantly more genome damage in the subfornic organ (SFO) than wild-type mice. The SFO is one of the few structures in the brain with an interrupted blood-brain barrier, which makes it accessible and particularly sensitive to circulating AT-II. In the recent literature, these genome damages were also observed in kidney and heart tissues and prove an additional genotoxicity of AT-II independent of AT1aR and consequently independent of blood pressure. In summary, this work shows that increased AT-II levels in neuronal cells cause genome damage due to NOX-produced superoxide. It is hoped that these results will one day help to decipher the complete development of VaD. N2 - In den letzten Jahrzehnten ist die Akzeptanz stetig größer geworden, dass oxidativer Stress eine bedeutende Rolle bei der Entstehung von chronischen Erkrankungen, malignen Neoplasien sowie der Beschleunigung des Alterungsprozesses spielt. Als eine der häufigsten chronischen Erkrankungen ist Hypertonie oft mit einem fehlregulierten Renin-Angiotensin-Aldosteron-System assoziiert, welches chronisch oxidativen Stress verursacht. Bluthochdruck ist ein Risikofaktor für neurologische Erkrankungen wie der vaskulären Demenz (VaD) und viele neurologischen Störungen, einschließlich der VaD, haben eine ROS-assoziierte beziehungsweise inflammatorische Komponente in ihrer Entstehung. Unsere Arbeitsgruppe konnte bereits eine AT-II-induzierte Genotoxizität in Nieren- und Myokardzellen bzw. -Gewebe nachweisen. Ziel dieser Dissertation war es, einen möglichen Zusammenhang zwischen AT-II und Neurodegeneration zu untersuchen, welche durch eine neuronale Genotoxizität von AT-II ausgelöst wird. Zunächst zeigten wir in zwei neuronalen Zelllinien, dass AT-II eine Dosis-abhängige Genomschädigung verursacht. Nachfolgende Experimente konnten diese Toxizität auf NOX-produziertes Superoxid zurückführen, das nach Bindung von AT-II an den AT1R generiert wird. Zudem konnte ein AT-II-induzierter Verbrauch des wichtigsten intrazellulären Antioxidans – Glutathion - nachgewiesen werden. In vivo konnten wir zeigen, dass AT1aR-Knockout-Mäuse nach AT-II-Behandlung signifikant mehr Genomschäden im Subfornikalorgan (SFO) aufwiesen als Wildtypmäuse. Das SFO hat als eine der wenigen Strukturen im Gehirn eine unterbrochene Blut-Hirn-Schranke, was es für zirkulierendes AT-II zugänglich und besonders empfindlich macht. Diese Genomschäden wurden in der neueren Literatur auch in Nieren- und Herzgewebe beschrieben und belegen eine zusätzliche, AT1aR- und damit Blutdruck-unabhängige Genotoxizität von AT-II. Zusammenfassend zeigt diese Arbeit, dass erhöhte AT-II-Konzentrationen in Nervenzellen Genomschäden durch NOX-produziertes Superoxid verursachen. Die Hoffnung ist, dass diese Ergebnisse dabei helfen, eines Tages die vollständige Entstehung der VaD zu entschlüsseln. KW - Angiotensin II KW - Toxizität KW - Neuronale KW - toxicity KW - angiotensin II KW - neuronal Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214273 ER -