Thomas Viel - Academia.edu (original) (raw)
Papers by Thomas Viel
Journal of Labelled Compounds and Radiopharmaceuticals, 2007
Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two ... more Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two singlestranded ribonucleic acids of short sequences, have been labelled with the positron-emitter fluorine-18 (T 1/2 : 109.8 min). The strategy involves (1) prosthetic conjugation of a single-stranded oligonucleotide with [ 18 F]FPyBrA (N-[3-(2-[ 18 F]fluoropyridin-3-yloxy)-propyl]-2-bromoacetamide) followed by (2) formation of the target duplex by annealing with the complementary sequence, therefore, permitting parallel and combinatorial preparation of [ 18 F]siRNAs. Pure fluorine-18-labelled siRNAs (0.55-1.11 GBq, specific activity: 74-148 GBq/mmol at EOB) could be obtained within 165 min starting from 37.0 GBq of starting [ 18 F]fluoride (1.5-3.0%, non-decay-corrected isolated yields).
Diagnostic and Interventional Imaging
Advances in Experimental Medicine and Biology
SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Here... more SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3Kγ activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as...
Nature Biomedical Engineering
Positron emission tomography-computed tomography (PET-CT) is the most sensitive molecular imaging... more Positron emission tomography-computed tomography (PET-CT) is the most sensitive molecular imaging modality, but it does not easily allow for rapid temporal acquisition. Ultrafast ultrasound imaging (UUI)-a recently introduced technology based on ultrasonic holography-leverages frame rates of up to several thousand images per second to quantitatively map, at high resolution, haemodynamic, biomechanical, electrophysiological and structural parameters. Here, we describe a pre-clinical scanner that registers PET-CT and UUI volumes acquired simultaneously and offers multiple combinations for imaging. We demonstrate that PET-CT-UUI allows for simultaneous images of the vasculature and metabolism during tumour growth in mice and rats, as well as for synchronized multi-modal cardiac cine-loops. Combined anatomical, functional and molecular imaging with PET-CT-UUI represents a high-performance and clinically translatable technology for biomedical research.
Physics in medicine and biology, Jan 21, 2018
We recently introduced a hybrid imaging instrument, PETRUS, based on a combination of positron em... more We recently introduced a hybrid imaging instrument, PETRUS, based on a combination of positron emission tomography (PET) for molecular imaging, x-ray computed tomography (CT) for anatomical imaging, co-registration and attenuation correction, and ultrafast ultrasound imaging (UUI) for motion-correction, hemodynamic and biomechanical imaging. In order to ensure a precise co-registration of simultaneous PET-UUI acquisitions, ultrasound probes attached to an ultrafast ultrasound scanner are operated in the field of view (FOV) of a small animal PET/CT scanner using a remote-controlled micro-positioner. Here we explore the effect of the presence of ultrasound probes on PET image quality. We compare the performance of PET and image quality with and without the presence of probes in the PET field of view, both in vitro following the NEMA-NU-4-2008 standard protocol, and in vivo in small animals. Overall, deviations in the quality of images acquired with and without the ultrasound probes we...
Nature medicine, 2018
The association between altered gut microbiota, intestinal permeability, inflammation and cardiom... more The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome and may promote atherosclerosis and vascular inflammation, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts trypto...
Nature communications, Nov 17, 2017
Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of ang... more Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes ...
Theranostics, 2017
The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardio... more The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardiovascular system. Here, we explored the cardiotoxicity of the antiangiogenic therapy, sunitinib, in the mouse heart from a diagnostic and therapeutic perspective. We showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis and reduced left ventricular ejection fraction as demonstrated by echocardiography. The capacity of positron emission tomography with [(18)F]fluorodeoxyglucose to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment. Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes. Co-...
![Research paper thumbnail of Preclinical Evidence That 3'-Deoxy-3'-[18F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy](https://attachments.academia-assets.com/74842345/thumbnails/1.jpg)
](Cancer research, Jan 15, 2016
Molecular imaging with the PET tracer 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) all... more Molecular imaging with the PET tracer 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) allows assessment of the proliferative state of organs in vivo Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [(18)F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [(18)F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs afte...
Journal of Visualized Experiments, 2017
In past years, the cell-sheet construct has spurred wide interest in regenerative medicine, espec... more In past years, the cell-sheet construct has spurred wide interest in regenerative medicine, especially for reconstructive surgery procedures. The development of diversified technologies combining adipose tissue-derived stromal cells (ADSCs) with various biomaterials has led to the construction of numerous types of tissue-engineered substitutes, such as bone, cartilage, and adipose tissues from rodent, porcine, or human ADSCs. Extended esophageal endoscopic submucosal dissection (ESD) is responsible for esophageal stricture formation. Stricture prevention remains challenging, with no efficient treatments available. Previous studies reported the effectiveness of mucosal cell-sheet transplantation in a canine model and in humans. ADSCs are attributed anti-inflammatory properties, local immune modulating effects, neovascularization induction, and differentiation abilities into mesenchymal and non-mesenchymal lineages. This original study describes the endoscopic transplantation of an ADSC tissue-engineered construct to prevent esophageal stricture in a swine model. The ADSC construct was composed of two allogenic ADSC sheets layered upon each other on a paper support membrane. The ADSCs were labeled with the PKH67 fluorophore to allow probe-based confocal laser endomicroscopy (pCLE) monitoring. On the day of transplantation, a 5-cm and hemi-circumferential ESD known to induce esophageal stricture was performed. Animals were immediately endoscopically transplanted with 4 ADSC constructs. The complete adhesion of the ADSC constructs was obtained after 10 min of gentle application. Animals were sacrificed on day 28. All animals were successfully transplanted. Transplantation was confirmed on day 3 with a positive pCLE evaluation. Compared to transplanted animals, control animals developed severe strictures, with major fibrotic tissue development, more frequent alimentary trouble, and reduced weight gain. In our model, the transplantation of allogenic ADSCs, organized in double cell sheets, after extended ESD was successful and strongly associated with a lower esophageal stricture rate.
Molecular Imaging, 2017
The value of combined L-(methyl-[ 11 C]) methionine positron-emitting tomography (MET-PET) and ma... more The value of combined L-(methyl-[ 11 C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n ¼ 65 patients with histologically verified brain lesions n ¼ 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software ''visualization and analysis framework volume rendering engine (Voreen)'' was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined by MET-PET (21.6 + 36.8 cm 3), T1w-Gd-MRI (3.9 + 7.8 cm 3), and FLAIR/T2-MRI (64.8 + 60.4 cm 3 ; P < .001). The MET-PET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8 + 35.0 cm 3 and without changes in FLAIR/T2 10.3 + 25.7 cm 3. FLAIR/T2-MRI visualized greatest tumor extent with differences to MET-PET being greater in posttherapy (64.6 + 62.7 cm 3) than in newly diagnosed patients (20.5 + 52.6 cm 3). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n ¼ 10 from other gliomas n ¼ 16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management.
European journal of nuclear medicine and molecular imaging, Jan 15, 2016
Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular ... more Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry. Treatment with BEV resulted in a pronounced decrease in tumour v...
Cancer research, Apr 30, 2017
The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammator... more The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, non-invasive imaging by positron emission tomography (PET) with [(18)F]DPA-714 (TSPO) and [(18)F]BR-351 (MMP) was used for assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([(18)F]FET) in conjunction with magnetic resonance imaging (MRI). We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4-1.7 fold with [(18)F]FET showing the biggest volume as depicted by a thresholding...
Klinische Neurophysiologie, 2011
Klinische Neurophysiologie
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2015
Stroke is the most common cause of death and disability from neurologic disease in humans. Activa... more Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography (μPET) using [(18)F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [(18)F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of crit...
Journal of Labelled Compounds and Radiopharmaceuticals, 2007
Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two ... more Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two singlestranded ribonucleic acids of short sequences, have been labelled with the positron-emitter fluorine-18 (T 1/2 : 109.8 min). The strategy involves (1) prosthetic conjugation of a single-stranded oligonucleotide with [ 18 F]FPyBrA (N-[3-(2-[ 18 F]fluoropyridin-3-yloxy)-propyl]-2-bromoacetamide) followed by (2) formation of the target duplex by annealing with the complementary sequence, therefore, permitting parallel and combinatorial preparation of [ 18 F]siRNAs. Pure fluorine-18-labelled siRNAs (0.55-1.11 GBq, specific activity: 74-148 GBq/mmol at EOB) could be obtained within 165 min starting from 37.0 GBq of starting [ 18 F]fluoride (1.5-3.0%, non-decay-corrected isolated yields).
Diagnostic and Interventional Imaging
Advances in Experimental Medicine and Biology
SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Here... more SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3Kγ activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as...
Nature Biomedical Engineering
Positron emission tomography-computed tomography (PET-CT) is the most sensitive molecular imaging... more Positron emission tomography-computed tomography (PET-CT) is the most sensitive molecular imaging modality, but it does not easily allow for rapid temporal acquisition. Ultrafast ultrasound imaging (UUI)-a recently introduced technology based on ultrasonic holography-leverages frame rates of up to several thousand images per second to quantitatively map, at high resolution, haemodynamic, biomechanical, electrophysiological and structural parameters. Here, we describe a pre-clinical scanner that registers PET-CT and UUI volumes acquired simultaneously and offers multiple combinations for imaging. We demonstrate that PET-CT-UUI allows for simultaneous images of the vasculature and metabolism during tumour growth in mice and rats, as well as for synchronized multi-modal cardiac cine-loops. Combined anatomical, functional and molecular imaging with PET-CT-UUI represents a high-performance and clinically translatable technology for biomedical research.
Physics in medicine and biology, Jan 21, 2018
We recently introduced a hybrid imaging instrument, PETRUS, based on a combination of positron em... more We recently introduced a hybrid imaging instrument, PETRUS, based on a combination of positron emission tomography (PET) for molecular imaging, x-ray computed tomography (CT) for anatomical imaging, co-registration and attenuation correction, and ultrafast ultrasound imaging (UUI) for motion-correction, hemodynamic and biomechanical imaging. In order to ensure a precise co-registration of simultaneous PET-UUI acquisitions, ultrasound probes attached to an ultrafast ultrasound scanner are operated in the field of view (FOV) of a small animal PET/CT scanner using a remote-controlled micro-positioner. Here we explore the effect of the presence of ultrasound probes on PET image quality. We compare the performance of PET and image quality with and without the presence of probes in the PET field of view, both in vitro following the NEMA-NU-4-2008 standard protocol, and in vivo in small animals. Overall, deviations in the quality of images acquired with and without the ultrasound probes we...
Nature medicine, 2018
The association between altered gut microbiota, intestinal permeability, inflammation and cardiom... more The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome and may promote atherosclerosis and vascular inflammation, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts trypto...
Nature communications, Nov 17, 2017
Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of ang... more Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes ...
Theranostics, 2017
The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardio... more The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardiovascular system. Here, we explored the cardiotoxicity of the antiangiogenic therapy, sunitinib, in the mouse heart from a diagnostic and therapeutic perspective. We showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis and reduced left ventricular ejection fraction as demonstrated by echocardiography. The capacity of positron emission tomography with [(18)F]fluorodeoxyglucose to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment. Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes. Co-...
Cancer research, Jan 15, 2016
Molecular imaging with the PET tracer 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) all... more Molecular imaging with the PET tracer 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) allows assessment of the proliferative state of organs in vivo Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [(18)F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [(18)F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs afte...
Journal of Visualized Experiments, 2017
In past years, the cell-sheet construct has spurred wide interest in regenerative medicine, espec... more In past years, the cell-sheet construct has spurred wide interest in regenerative medicine, especially for reconstructive surgery procedures. The development of diversified technologies combining adipose tissue-derived stromal cells (ADSCs) with various biomaterials has led to the construction of numerous types of tissue-engineered substitutes, such as bone, cartilage, and adipose tissues from rodent, porcine, or human ADSCs. Extended esophageal endoscopic submucosal dissection (ESD) is responsible for esophageal stricture formation. Stricture prevention remains challenging, with no efficient treatments available. Previous studies reported the effectiveness of mucosal cell-sheet transplantation in a canine model and in humans. ADSCs are attributed anti-inflammatory properties, local immune modulating effects, neovascularization induction, and differentiation abilities into mesenchymal and non-mesenchymal lineages. This original study describes the endoscopic transplantation of an ADSC tissue-engineered construct to prevent esophageal stricture in a swine model. The ADSC construct was composed of two allogenic ADSC sheets layered upon each other on a paper support membrane. The ADSCs were labeled with the PKH67 fluorophore to allow probe-based confocal laser endomicroscopy (pCLE) monitoring. On the day of transplantation, a 5-cm and hemi-circumferential ESD known to induce esophageal stricture was performed. Animals were immediately endoscopically transplanted with 4 ADSC constructs. The complete adhesion of the ADSC constructs was obtained after 10 min of gentle application. Animals were sacrificed on day 28. All animals were successfully transplanted. Transplantation was confirmed on day 3 with a positive pCLE evaluation. Compared to transplanted animals, control animals developed severe strictures, with major fibrotic tissue development, more frequent alimentary trouble, and reduced weight gain. In our model, the transplantation of allogenic ADSCs, organized in double cell sheets, after extended ESD was successful and strongly associated with a lower esophageal stricture rate.
Molecular Imaging, 2017
The value of combined L-(methyl-[ 11 C]) methionine positron-emitting tomography (MET-PET) and ma... more The value of combined L-(methyl-[ 11 C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n ¼ 65 patients with histologically verified brain lesions n ¼ 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software ''visualization and analysis framework volume rendering engine (Voreen)'' was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined by MET-PET (21.6 + 36.8 cm 3), T1w-Gd-MRI (3.9 + 7.8 cm 3), and FLAIR/T2-MRI (64.8 + 60.4 cm 3 ; P < .001). The MET-PET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8 + 35.0 cm 3 and without changes in FLAIR/T2 10.3 + 25.7 cm 3. FLAIR/T2-MRI visualized greatest tumor extent with differences to MET-PET being greater in posttherapy (64.6 + 62.7 cm 3) than in newly diagnosed patients (20.5 + 52.6 cm 3). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n ¼ 10 from other gliomas n ¼ 16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management.
European journal of nuclear medicine and molecular imaging, Jan 15, 2016
Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular ... more Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry. Treatment with BEV resulted in a pronounced decrease in tumour v...
Cancer research, Apr 30, 2017
The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammator... more The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, non-invasive imaging by positron emission tomography (PET) with [(18)F]DPA-714 (TSPO) and [(18)F]BR-351 (MMP) was used for assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([(18)F]FET) in conjunction with magnetic resonance imaging (MRI). We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4-1.7 fold with [(18)F]FET showing the biggest volume as depicted by a thresholding...
Klinische Neurophysiologie, 2011
Klinische Neurophysiologie
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2015
Stroke is the most common cause of death and disability from neurologic disease in humans. Activa... more Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography (μPET) using [(18)F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [(18)F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of crit...