Showing papers by "Tobias Bäuerle published in 2022"
TL;DR: In this article , the authors presented the first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in systemic sclerosis-related MF and may be a diagnostic option to monitor cardiac fibroblasts activity in situ.
Abstract: Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([68Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF.In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [68Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated.[68Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [68Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP+ fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [68Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [68Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [68Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage.We present first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.
7 citations
TL;DR: In this article , the authors reported strong sex-dimorphisms for central, but not for peripheral mechanisms of sphingomyelinase 2 (NSM) action in mouse models and found that reduced NSM activity increased depression and anxiety-like behavior, but was not involved in alcohol use for selfmanagement of the emotional state.
Abstract: Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
6 citations
TL;DR: The principles underlying RECIST, as well as their reproducibility and limitations, are discussed, which suggest that measurement automation is desirable and potentially reduces the variability of results, but associated technical difficulties must be overcome, and human adjudications may be required.
Abstract: Response evaluation criteria in solid tumours (RECIST) v1.1 are currently the reference standard for evaluating efficacy of therapies in patients with solid tumours who are included in clinical trials, and they are widely used and accepted by regulatory agencies. This expert statement discusses the principles underlying RECIST, as well as their reproducibility and limitations. While the RECIST framework may not be perfect, the scientific bases for the anticancer drugs that have been approved using a RECIST-based surrogate endpoint remain valid. Importantly, changes in measurement have to meet thresholds defined by RECIST for response classification within thus partly circumventing the problems of measurement variability. The RECIST framework also applies to clinical patients in individual settings even though the relationship between tumour size changes and outcome from cohort studies is not necessarily translatable to individual cases. As reproducibility of RECIST measurements is impacted by reader experience, choice of target lesions and detection/interpretation of new lesions, it can result in patients changing response categories when measurements are near threshold values or if new lesions are missed or incorrectly interpreted. There are several situations where RECIST will fail to evaluate treatment-induced changes correctly; knowledge and understanding of these is crucial for correct interpretation. Also, some patterns of response/progression cannot be correctly documented by RECIST, particularly in relation to organ-site (e.g. bone without associated soft-tissue lesion) and treatment type (e.g. focal therapies). These require specialist reader experience and communication with oncologists to determine the actual impact of the therapy and best evaluation strategy. In such situations, alternative imaging markers for tumour response may be used but the sources of variability of individual imaging techniques need to be known and accounted for. Communication between imaging experts and oncologists regarding the level of confidence in a biomarker is essential for the correct interpretation of a biomarker and its application to clinical decision-making. Though measurement automation is desirable and potentially reduces the variability of results, associated technical difficulties must be overcome, and human adjudications may be required.
6 citations
TL;DR: The proportion of SMM patients suffering from end‐organ damage at progression to MM was reduced by one third under the updated disease definition, and whole‐body magnetic resonance imaging is an important tool for detection ofSMM patients who progress to MM without end-organ damage.
Abstract: The definition of multiple myeloma (MM) was updated in 2014, with the intent to enable earlier treatment and thereby avoid appearance of end‐organ damage at progression from smouldering multiple myeloma (SMM) to MM. The purpose of this study was to investigate to which extent the development of end‐organ damage at progression to MM was reduced under the updated guidelines. In this prospective observational cohort study (ClinicalTrials.gov Identifier: NCT01374412), between 2014 and 2020, 96 SMM patients prospectively underwent whole‐body magnetic resonance imaging (wb‐MRI) and serological follow‐up at baseline and every 6 months thereafter. A total of 22 patients progressed into MM during follow‐up, of which seven (32%) showed SLiM‐criteria only but no end‐organ damage. Four (57%) of the seven patients who progressed by SLiM‐criteria only progressed with >1 focal lesion (FL) or a growing FL, and three (43%) due to serum free light‐chain‐ratio ≥100. Fifteen (68%) out of 22 patients who progressed still suffered from end‐organ damage at progression. The updated disease definition reduced the proportion of SMM patients suffering from end‐organ damage at progression to MM by one third. wb‐MRI is an important tool for detection of SMM patients who progress to MM without end‐organ damage.
4 citations
TL;DR: This study developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone, and proposes that this model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors.
Abstract: Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate–fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors.
3 citations
TL;DR: In this paper , the impact of the MRI acquisition setup and registration method was evaluated in the context of brain RT, both geometrically and dosimetrically, and three different automatic registration tools provided by three treatment planning systems were used to rigidly register both MRIs and CT in addition to the clinical registration.
Abstract: In MR-based radiotherapy (RT), MRI images are co-registered to the planning CT to leverage MR image information for RT planning. Especially in brain stereotactic RT, where typical CTV-PTV margins are 1-2 mm, high registration accuracy is critical. Several factors influence the registration accuracy, including the acquisition setup during MR simulation and the registration methods.In this work, the impact of the MRI acquisition setup and registration method was evaluated in the context of brain RT, both geometrically and dosimetrically.MRI of 20 brain radiotherapy patients was acquired in two MRI acquisition setups (RT and diagnostic). Three different automatic registration tools provided by three treatment planning systems were used to rigidly register both MRIs and CT in addition to the clinical registration. Segmentation-based evaluation using Hausdorff Distance (HD)/Dice Similarity Coefficient and landmark-based evaluation were used as evaluation metrics. Dose-volume-histograms were evaluated for target volumes and various organs at risks.MRI acquisition in the RT setup provided a similar head extension as compared to the planning CT. The registration method had a more significant influence than the acquisition setup (Wilcoxon signed-rank test, p<0.05). When registering using a less optimal registration method, the RT setup improved the registration accuracy compared to the diagnostic setup (Difference: ΔMHD = 0.16 mm, ΔHDP95 = 0.64 mm, mean Euclidean distance (ΔmEuD) = 2.65 mm). Different registration methods and acquisition setups lead to the variation of the clinical DVH. Acquiring MRI in the RT setup can improve PTV and GTV coverage compared to the diagnostic setup.Both MRI acquisition setup and registration method influence the MRI-CT registration accuracy in brain RT patients geometrically and dosimetrically. MR-simulation in the RT setup assures optimal registration accuracy if automatic registration is impaired, and therefore recommended for brain RT.
2 citations
TL;DR: It is shown that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model and elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR 4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that s CD83 acts via the TRIF-signaling cascade.
Abstract: Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1β, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP+ osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
2 citations
TL;DR: In this article , CAR T-cells were analyzed with flow cytometry utilizing a two step-staining with a biotinylated CD19 protein to detect the CAR T cell levels at day 7.
1 citations
TL;DR: The AV loop is a powerful tool for vascularization which is independent from scaffold cellularization with endothelial progenitor cells’ prior implantation and was able to prove a strong scaffold vascularization in all groups.
Abstract: The microvascular endothelial network plays an important role in osteogenesis, bone regeneration and bone tissue engineering. Endothelial progenitor cells (EPCs) display a high angiogenic and vasculogenic potential. The endothelialization of scaffolds with endothelial progenitor cells supports vascularization and tissue formation. In addition, EPCs enhance the osteogenic differentiation and bone formation of mesenchymal stem cells (MSCs). This study aimed to investigate the impact of EPCs on vascularization and bone formation of a hydroxyapatite (HA) and beta-tricalcium phosphate (ß-TCP)–fibrin scaffold. Three groups were designed: a scaffold-only group (A), a scaffold and EPC group (B), and a scaffold and EPC/MSC group (C). The HA/ß–TCP–fibrin scaffolds were placed in a porous titanium chamber permitting extrinsic vascularization from the surrounding tissue. Additionally, intrinsic vascularization was achieved by means of an arteriovenous loop (AV loop). After 12 weeks, the specimens were explanted and investigated by histology and CT. We were able to prove a strong scaffold vascularization in all groups. No differences regarding the vessel number and density were detected between the groups. Moreover, we were able to prove bone formation in the coimplantation group. Taken together, the AV loop is a powerful tool for vascularization which is independent from scaffold cellularization with endothelial progenitor cells’ prior implantation.
1 citations
TL;DR: Non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT).
Abstract: Simple Summary The bone marrow microenvironment, particularly adipocytes, plays a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. In this prospective longitudinal study, we used multimodal and multiparametric imaging from magnetic resonance (MRI) and hybrid imaging (positron emission tomography and computed tomography; PET/CT) to non-invasively characterize the pathophysiologic processes of experimental bone metastases in obese and non-obese individuals. Obesity was induced by a high-fat diet (HFD) in rats and mice, resulting in enhanced glucose metabolism and angiogenic activity in metastatic bone lesions, as shown by significantly increased dynamic contrast-enhanced MRI and [18F]fluorodeoxyglucose PET/CT parameters in HFD-fed animals. These results were validated with immunohistochemistry and gene expression analysis. In conclusion, pathophysiological processes can be non-invasively assessed by MRI and PET/CT, opening novel avenues for quantitative assessment of follow-up and monitoring of treatment response in skeletal lesions. Abstract The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and µPET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [18F]fluorodeoxyglucose-PET/CT([18F]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [18F]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [18F]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [18F]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [18F]FDG-PET/CT.
TL;DR: In this article , a 24-jährigen patient with anhaltenden Oberbauchschmerzen, Übelkeit, Völlegefühl, and Völschmerzhaftigkeit vorstellte.
Abstract: Zusammenfassung Wir berichten über einen 24-jährigen Patienten, der sich mit anhaltenden Oberbauchschmerzen, Übelkeit und Völlegefühl ohne Erbrechen seit 5 Monaten zur ambulanten endoskopischen Diagnostik vorstellte. Bei der körperlichen Untersuchung fiel eine Verhärtung im Epigastrium ohne Druckschmerzhaftigkeit auf. Endoskopisch zeigte sich lediglich eine Impression des Bulbus duodeni bei intakter Duodenalschleimhaut. Darüber hinaus lagen unauffällige Befunde in Gastroskopie und Ileokoloskopie vor. Abdomensonografisch zeigte sich im linken Leberlappen eine große inhomogene Raumforderung mit scharfer, unregelmäßiger Begrenzung. Der rechte Leberlappen wies eine komplett unauffällige Sonomorphologie auf, insbesondere keine Zeichen des Parenchymschadens oder einer Leberzirrhose. Entlang der oberen mesenterialen Gefäße stellten sich mehrere vergrößerte Lymphknoten mit Kontakt zum Bulbus duodeni dar. In der Kontrastmittelsonografie (CE-US) zeigte die Leberläsion das typische Perfusionsmuster eines hepatozellulären Karzinoms. Zur Klärung des malignitätsverdächtigen Befunds wurde eine sonografisch gesteuerte Stanzbiopsie durchgeführt. Die histopathologische Aufarbeitung ergab den Befund eines hepatozellulären Karzinoms vom fibrolamellären Subtyp. Mit diesem Fallbericht möchten wir zeigen, dass das HCC vom fibrolamellären Subtyp, trotz einer starken kollagenreichen bindegewebigen Stromakomponente in der Histopathologie, ein HCC-typisches Perfusionsmuster in der KM-Sonografie aufweist.