TY - JOUR A1 - Proetel, Ulrike A1 - Pletsch, Nadine A1 - Lauseker, Michael A1 - Müller, Martin C. A1 - Hanfstein, Benjamin A1 - Krause, Stefan W. A1 - Kalmanti, Lida A1 - Schreiber, Annette A1 - Heim, Dominik A1 - Baerlocher, Gabriela M. A1 - Hofmann, Wolf-Karsten A1 - Lange, Elisabeth A1 - Einsele, Hermann A1 - Wernli, Martin A1 - Kremers, Stephan A1 - Schlag, Rudolf A1 - Müller, Lothar A1 - Hänel, Mathias A1 - Link, Hartmut A1 - Hertenstein, Bernd A1 - Pfirrmann, Markus A1 - Hochhaus, Andreas A1 - Hasford, Joerg A1 - Hehlmann, Rüdiger A1 - Saußele, Susanne T1 - Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV JF - Annals of Hematology N2 - The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874 KW - chronic myeloid leukemia KW - older patients KW - different imatinib dose regimens KW - early applied higher imatinib dosages Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121574 SN - 0939-5555 VL - 93 IS - 7 ER - TY - JOUR A1 - Kasang, Christa A1 - Kalluvya, Samuel A1 - Majinge, Charles A1 - Kongola, Gilbert A1 - Mlewa, Mathias A1 - Massawe, Irene A1 - Kabyemera, Rogatus A1 - Magambo, Kinanga A1 - Ulmer, Albrecht A1 - Klinker, Hartwig A1 - Gschmack, Eva A1 - Horn, Anne A1 - Koutsilieri, Eleni A1 - Preiser, Wolfgang A1 - Hofmann, Daniela A1 - Hain, Johannes A1 - Müller, Andreas A1 - Dölken, Lars A1 - Weissbrich, Benedikt A1 - Rethwilm, Axel A1 - Stich, August A1 - Scheller, Carsten T1 - Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial JF - PLoS One N2 - Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection. KW - HIV KW - immune activation KW - viral load KW - drug adherence KW - viral replication KW - AIDS KW - HIV infections KW - highly-active antiretroviral therapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146479 VL - 11 IS - 1 ER - TY - JOUR A1 - Tony, Hans-Peter A1 - Burmester, Gerd A1 - Schulze-Koops, Hendrik A1 - Grunke, Mathias A1 - Henes, Joerg A1 - Kötter, Ina A1 - Haas, Judith A1 - Unger, Leonore A1 - Lovric, Svjetlana A1 - Haubitz, Marion A1 - Fischer-Betz, Rebecca A1 - Chehab, Gamal A1 - Rubbert-Roth, Andrea A1 - Specker, Christof A1 - Weinerth, Jutta A1 - Holle, Julia A1 - Müller-Ladner, Ulf A1 - König, Ramona A1 - Fiehn, Christoph A1 - Burgwinkel, Philip A1 - Budde, Klemens A1 - Sörensen, Helmut A1 - Meurer, Michael A1 - Aringer, Martin A1 - Kieseier, Bernd A1 - Erfurt-Berge, Cornelia A1 - Sticherling, Michael A1 - Veelken, Roland A1 - Ziemann, Ulf A1 - Strutz, Frank A1 - von Wussow, Praxis A1 - Meier, Florian MP A1 - Hunzelmann, Nico A1 - Schmidt, Enno A1 - Bergner, Raoul A1 - Schwarting, Andreas A1 - Eming, Rüdiger A1 - Schwarz-Eywill, Michael A1 - Wassenberg, Siegfried A1 - Fleck, Martin A1 - Metzler, Claudia A1 - Zettl, Uwe A1 - Westphal, Jens A1 - Heitmann, Stefan A1 - Herzog, Anna L. A1 - Wiendl, Heinz A1 - Jakob, Waltraud A1 - Schmidt, Elvira A1 - Freivogel, Klaus A1 - Dörner, Thomas A1 - Hertl, Michael A1 - Stadler, Rudolf T1 - Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) JF - Arthritis Research & Therapy N2 - Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm) KW - GRAID Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142856 VL - 13 IS - R75 ER - TY - JOUR A1 - Ewald, Heike A1 - Glotzbach-Schoon, Evelyn A1 - Gerdes, Antje B. M. A1 - Andreatta, Marta A1 - Müller, Mathias A1 - Mühlberger, Andreas A1 - Pauli, Paul T1 - Delay and trace fear conditioning in a complex virtual learning environment - neural substrates of extinction JF - Frontiers in Human Neuroscience N2 - Extinction is an important mechanism to inhibit initially acquired fear responses. There is growing evidence that the ventromedial prefrontal cortex (vmPFC) inhibits the amygdala and therefore plays an important role in the extinction of delay fear conditioning. To our knowledge, there is no evidence on the role of the prefrontal cortex in the extinction of trace conditioning up to now. Thus, we compared brain structures involved in the extinction of human delay and trace fear conditioning in a between-subjects-design in an fMRI study. Participants were passively guided through a virtual environment during learning and extinction of conditioned fear. Two different lights served as conditioned stimuli (CS); as unconditioned stimulus (US) a mildly painful electric stimulus was delivered. In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), whereas in the trace conditioning group (TCG) the US was presented 4s after CS+ offset. Both groups showed insular and striatal activation during early extinction, but differed in their prefrontal activation. The vmPFC was mainly activated in the DCG, whereas the TCG showed activation of the dorsolateral prefrontal cortex (dlPFC) during extinction. These results point to different extinction processes in delay and trace conditioning. VmPFC activation during extinction of delay conditioning might reflect the inhibition of the fear response. In contrast, dlPFC activation during extinction of trace conditioning may reflect modulation of working memory processes which are involved in bridging the trace interval and hold information in short term memory. KW - prefrontal cortex KW - delay conditioning KW - trace conditioning KW - extinction KW - virtual reality KW - fMRI KW - medial prefrontal cortex KW - event-related FMRI KW - orbifrontal cortex KW - contextual fear Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116230 SN - 1662-5161 VL - 8 IS - 323 ER - TY - JOUR A1 - Hanfstein, Benjamin A1 - Lauseker, Michael A1 - Hehlmann, Rüdiger A1 - Saussele, Susanne A1 - Erben, Philipp A1 - Dietz, Christian A1 - Fabarius, Alice A1 - Proetel, Ulrike A1 - Schnittger, Susanne A1 - Haferlach, Claudia A1 - Krause, Stefan W. A1 - Schubert, Jörg A1 - Einsele, Hermann A1 - Hänel, Mathias A1 - Dengler, Jolanta A1 - Falge, Christiane A1 - Kanz, Lothar A1 - Neubauer, Andreas A1 - Kneba, Michael A1 - Stengelmann, Frank A1 - Pfreundschuh, Michael A1 - Waller, Cornelius F. A1 - Spiekerman, Karsten A1 - Baerlocher, Gabriela M. A1 - Pfirrmann, Markus A1 - Hasford, Joerg A1 - Hofmann, Wolf-Karsten A1 - Hochhaus, Andreas A1 - Müller, Martin C. T1 - Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib JF - Haematologica N2 - The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874) KW - chronic myelogenous leukemia KW - polymerase-chain-reaktion KW - hybrid messenger RNA KW - chronic phase KW - cytogenetic response KW - no correlation KW - ABL gene KW - transcripts KW - breakpoint KW - survival Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115476 SN - 1592-8721 VL - 99 IS - 9 ER - TY - JOUR A1 - Gromer, Daniel A1 - Madeira, Octávia A1 - Gast, Philipp A1 - Nehfischer, Markus A1 - Jost, Michael A1 - Müller, Mathias A1 - Mühlberger, Andreas A1 - Pauli, Paul T1 - Height Simulation in a Virtual Reality CAVE System: Validity of Fear Responses and Effects of an Immersion Manipulation JF - Frontiers in Human Neuroscience N2 - Acrophobia is characterized by intense fear in height situations. Virtual reality (VR) can be used to trigger such phobic fear, and VR exposure therapy (VRET) has proven effective for treatment of phobias, although it remains important to further elucidate factors that modulate and mediate the fear responses triggered in VR. The present study assessed verbal and behavioral fear responses triggered by a height simulation in a 5-sided cave automatic virtual environment (CAVE) with visual and acoustic simulation and further investigated how fear responses are modulated by immersion, i.e., an additional wind simulation, and presence, i.e., the feeling to be present in the VE. Results revealed a high validity for the CAVE and VE in provoking height related self-reported fear and avoidance behavior in accordance with a trait measure of acrophobic fear. Increasing immersion significantly increased fear responses in high height anxious (HHA) participants, but did not affect presence. Nevertheless, presence was found to be an important predictor of fear responses. We conclude that a CAVE system can be used to elicit valid fear responses, which might be further enhanced by immersion manipulations independent from presence. These results may help to improve VRET efficacy and its transfer to real situations. KW - anxiety KW - fear behavior KW - virtual reality KW - presence KW - immersion KW - acrophobia Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196113 SN - 1662-5161 VL - 12 IS - 372 ER - TY - JOUR A1 - Eckardt, Jan-Niklas A1 - Stasik, Sebastian A1 - Kramer, Michael A1 - Röllig, Christoph A1 - Krämer, Alwin A1 - Scholl, Sebastian A1 - Hochhaus, Andreas A1 - Crysandt, Martina A1 - Brümmendorf, Tim H. A1 - Naumann, Ralph A1 - Steffen, Björn A1 - Kunzmann, Volker A1 - Einsele, Hermann A1 - Schaich, Markus A1 - Burchert, Andreas A1 - Neubauer, Andreas A1 - Schäfer-Eckart, Kerstin A1 - Schliemann, Christoph A1 - Krause, Stefan W. A1 - Herbst, Regina A1 - Hänel, Mathias A1 - Frickhofen, Norbert A1 - Noppeney, Richard A1 - Kaiser, Ulrich A1 - Baldus, Claudia D. A1 - Kaufmann, Martin A1 - Rácil, Zdenek A1 - Platzbecker, Uwe A1 - Berdel, Wolfgang E. A1 - Mayer, Jiří A1 - Serve, Hubert A1 - Müller-Tidow, Carsten A1 - Ehninger, Gerhard A1 - Stölzel, Friedrich A1 - Kroschinsky, Frank A1 - Schetelig, Johannes A1 - Bornhäuser, Martin A1 - Thiede, Christian A1 - Middeke, Jan Moritz T1 - Loss-of-function mutations of BCOR are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia JF - Cancers N2 - Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation. KW - acute myeloid leukemia KW - BCOR KW - BCORL1 KW - loss-of-function KW - risk stratification KW - survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236735 SN - 2072-6694 VL - 13 IS - 9 ER - TY - JOUR A1 - Rodrigues, Johannes A1 - Ziebell, Philipp A1 - Müller, Mathias A1 - Hewig, Johannes T1 - Standardizing continuous data classifications in a virtual T-maze using two-layer feedforward networks JF - Scientific Reports N2 - There continues to be difficulties when it comes to replication of studies in the field of Psychology. In part, this may be caused by insufficiently standardized analysis methods that may be subject to state dependent variations in performance. In this work, we show how to easily adapt the two-layer feedforward neural network architecture provided by Huang1 to a behavioral classification problem as well as a physiological classification problem which would not be solvable in a standardized way using classical regression or “simple rule” approaches. In addition, we provide an example for a new research paradigm along with this standardized analysis method. This paradigm as well as the analysis method can be adjusted to any necessary modification or applied to other paradigms or research questions. Hence, we wanted to show that two-layer feedforward neural networks can be used to increase standardization as well as replicability and illustrate this with examples based on a virtual T-maze paradigm\(^{2−5}\) including free virtual movement via joystick and advanced physiological data signal processing. KW - standardized analysis method KW - neural network architecture KW - two‑layer feedforward networks Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301096 VL - 12 IS - 1 ER -