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1.
Hendrik Kröning Thomas Göhler Thomas Decker Marc Grundeis Georgi Kojouharoff Jörg Lipke Dieter Semsek Enno Moorahrend Annette Sauer Harald-Robert Bruch Rüdiger Liersch Arnd Nusch Ursula Vehling-Kaiser Manfred Welslau Ralf Grunewald Hanns-Detlev Harich Marcel Stephany Jens Uhlig Rebecca de Buhr Melanie Frank Cathrin Hogrefe Norbert Marschner Karin Potthoff Frank Hartmann Timo Reisländer Ingo Schwaner 《International journal of cancer. Journal international du cancer》2023,153(6):1227-1240
The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice. 相似文献
2.
Theresa M. Thole Joern Toedling Annika Sprüssel Sebastian Pfeil Larissa Savelyeva David Capper Clemens Messerschmidt Dieter Beule Stefanie Groeneveld-Krentz Cornelia Eckert Guido Gambara Anton G. Henssen Sabine Finkler Johannes H. Schulte Anja Sieber Nils Bluethgen Christian R. A. Regenbrecht Annette Künkele Marco Lodrini Angelika Eggert Hedwig E. Deubzer 《International journal of cancer. Journal international du cancer》2020,146(4):1031-1041
Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system. 相似文献
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Lukas Frase Peter Selhausen Lukas Krone Sulamith Tsodor Friederike Jahn Bernd Feige Jonathan G. Maier Florian Mainberger Hannah Piosczyk Marion Kuhn Stefan Klöppel Annette Sterr Chiara Baglioni Kai Spiegelhalder Dieter Riemann Michael A. Nitsche Christoph Nissen 《Brain stimulation》2019,12(3):674-683
Background
Arousal and sleep represent basic domains of behavior, and alterations are of high clinical importance.Objective/hypothesis
The aim of this study was to further elucidate the neurobiology of insomnia disorder (ID) and the potential for new treatment developments, based on the modulation of cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS). Specifically, we tested the hypotheses that bi-frontal anodal tDCS shortens and cathodal tDCS prolongs total sleep time in patients with ID, compared to sham stimulation. Furthermore, we tested for differences in indices of arousal between ID patients and healthy controls and explored their potential impact on tDCS effects.Methods
Nineteen ID patients underwent a within-subject repeated-measures sleep laboratory study with adaptation, baseline and three experimental nights. Bifrontal anodal, cathodal and sham tDCS was delivered in a counterbalanced order immediately prior to sleep. Wake EEG was recorded prior to and after tDCS as well as on the following morning. Subsequently, we compared patients with ID to a healthy control group from an earlier dataset.Results
Against our hypothesis, we did not observe any tDCS effects on sleep continuity or sleep architecture in patients with ID. Further analyses of nights without stimulation demonstrated significantly increased levels of arousal in ID patients compared to healthy controls, as indexed by subjective reports, reduced total sleep time, increased wake after sleep onset and increased high frequency EEG power during wakefulness and NREM sleep. Of note, indices of increased arousal predicted the lack of effect of tDCS in ID patients.Conclusions
Our study characterizes for the first time differential effects of tDCS on sleep in patients with ID and healthy controls, presumably related to persistent hyperarousal in ID. These findings suggest that adapted tDCS protocols need to be developed to modulate arousal and sleep dependent on baseline arousal levels. 相似文献5.
Lino Möhrmann Martina K. Zowada Hendrik Strakerjahn Christine Siegl Annette Kopp-Schneider Damir Krunic Dirk Strunk Martin Schneider Mark Kriegsmann Katharina Kriegsmann Friederike Herbst Claudia R. Ball Hanno Glimm Sebastian M. Dieter 《International journal of cancer. Journal international du cancer》2020,147(2):519-531
Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones—a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity. 相似文献
6.
Lukas Frase Wolfram Regen Stphanie Kass Albena Rambach Chiara Baglioni Bernd Feige Jürgen Hennig Dieter Riemann Christoph Nissen Kai Spiegelhalder 《Journal of sleep research》2020,29(5)
The current study was designed to further clarify the influence of brain morphology, sleep oscillatory activity and age on memory consolidation. Specifically, we hypothesized, that a smaller volume of hippocampus, parahippocampal and medial prefrontal cortex negatively impacts declarative, but not procedural, memory consolidation. Explorative analyses were conducted to demonstrate whether a decrease in slow‐wave activity negatively impacts declarative memory consolidation, and whether these factors mediate age effects on memory consolidation. Thirty‐eight healthy participants underwent an acquisition session in the evening and a retrieval session in the morning after night‐time sleep with polysomnographic monitoring. Declarative memory was assessed with the paired‐associate word list task, while procedural memory was tested using the mirror‐tracing task. All participants underwent high‐resolution magnetic resonance imaging. Participants with smaller hippocampal, parahippocampal and medial prefrontal cortex volumes displayed a reduced overnight declarative, but not procedural memory consolidation. Mediation analyses showed significant age effects on overnight declarative memory consolidation, but no significant mediation effects of brain morphology on this association. Further mediation analyses showed that the effects of age and brain morphology on overnight declarative memory consolidation were not mediated by polysomnographic variables or sleep electroencephalogram spectral power variables. Thus, the results suggest that the association between age, specific brain area volume and overnight memory consolidation is highly relevant, but does not necessarily depend on slow‐wave sleep as previously conceptualized. 相似文献
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9.
Hendrik Fritsche Thorsten Heilmann Robert J. Tower Charlotte Hauser Anja von Au Doaa El-Sheikh Graeme M. Campbell G?hkan Alp Denis Schewe Sebastian Hübner Sanjay Tiwari Daniel Kownatzki Susann Boretius Dieter Adam Walter Jonat Thomas Becker Claus C. Glüer Margot Z?ller Holger Kalthoff Christian Schem Anna Trauzold 《Oncotarget》2015,6(11):9502-9516
Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases. 相似文献
10.
Paula Hoff Daniel L Belavy D?rte Huscher Annemarie Lang Martin Hahne Anne-Kathrin Kuhlmey Patrick Maschmeyer Gabriele Armbrecht Rudolf Fitzner Frank H Perschel Timo Gaber Gerd-Rüdiger Burmester Rainer H Straub Dieter Felsenberg Frank Buttgereit 《Cellular & molecular immunology》2015,12(4):483-492
Exercise at regular intervals is assumed to have a positive effect on immune functions. Conversely, after spaceflight and under simulated weightlessness (e.g., bed rest), immune functions can be suppressed. We aimed to assess the effects of simulated weightlessness (Second Berlin BedRest Study; BBR2-2) on immunological parameters and to investigate the effect of exercise (resistive exercise with and without vibration) on these changes. Twenty-four physically and mentally healthy male volunteers (20–45 years) performed resistive vibration exercise (n=7), resistance exercise without vibration (n=8) or no exercise (n=9) within 60 days of bed rest. Blood samples were taken 2 days before bed rest, on days 19 and 60 of bed rest. Composition of immune cells was analyzed by flow cytometry. Cytokines and neuroendocrine parameters were analyzed by Luminex technology and ELISA/RIA in plasma. General changes over time were identified by paired t-test, and exercise-dependent effects by pairwise repeated measurements (analysis of variance (ANOVA)). With all subjects pooled, the number of granulocytes, natural killer T cells, hematopoietic stem cells and CD45RA and CD25 co-expressing T cells increased and the number of monocytes decreased significantly during the study; the concentration of eotaxin decreased significantly. Different impacts of exercise were seen for lymphocytes, B cells, especially the IgD+ subpopulation of B cells and the concentrations of IP-10, RANTES and DHEA-S. We conclude that prolonged bed rest significantly impacts immune cell populations and cytokine concentrations. Exercise was able to specifically influence different immunological parameters. In summary, our data fit the hypothesis of immunoprotection by exercise and may point toward even superior effects by resistive vibration exercise. 相似文献