Publications by authors named "Thomas Lindner"

94 Publications

Radioligands Targeting Fibroblast Activation Protein (FAP).

Cancers (Basel) 2021 Nov 16;13(22). Epub 2021 Nov 16.

Department of Nuclear Medicine, University Hospital Würzburg, 97080 Würzburg, Germany.

Targeting fibroblast activation protein (FAP) in cancer-associated fibroblasts (CAFs) has attracted significant attention in nuclear medicine. Since these cells are present in most cancerous tissues and FAP is rarely expressed in healthy tissues, anti-FAP tracers have a potential as pan-tumor agents. Compared to the standard tumor tracer [F]FDG, these tracers show better tumor-to-background ratios (TBR) in many indications. Unlike [F]FDG, FAP-targeted tracers do not require exhausting preparations, such as dietary restrictions on the part of the patient, and offer the possibility of radioligand therapy (RLT) in a theragnostic approach. Although a radiolabeled antibody was clinically investigated as early as the 1990s, the breakthrough event for FAP-targeting in nuclear medicine was the introduction and clinical application of the so-called FAPI-tracers in 2018. From then, the development and application of FAP-targeted tracers became hot topics for the radiopharmaceutical and nuclear medicine community, and attracted the interest of pharmaceutical companies. The aim of this review is to provide a comprehensive overview of the development of FAP-targeted radiopharmaceuticals and their application in nuclear medicine.
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http://dx.doi.org/10.3390/cancers13225744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616197PMC
November 2021

Measurements of Functional Network Connectivity Using Resting State Arterial Spin Labeling During Neurosurgery.

World Neurosurg 2022 01 18;157:152-158. Epub 2021 Oct 18.

Department of Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Campus Kiel, Germany; Neurorad.ch, Zurich, Switzerland; Neuroradiology, Department of Radiology and Nuclear Medicine, Kantonsspital, Winterthur, Switzerland.

In neurosurgery, an exact delineation of functional areas is of great interest to spare important regions to ensure the best possible outcome for the patient (i.e., maximum removal while maintaining the highest possible quality of life). Preoperative imaging is routinely performed, including the visualization of not only structural but also functional information. During surgery, however, brain shift can occur, leading to an offset between the previously defined and the real position. Real-time imaging during the procedure is therefore desired to obtain this information while performing surgery. In this study 15 patients suffering from glioblastoma multiforme were included. These patients underwent structural and perfusion imaging using arterial spin labeling during the procedure. The latter has been used for gathering information about tumor residual perfusion. However, special postprocessing of this data allows for additional mapping of resting state networks and is intended to be used to gather deeper insights to aid the surgeon in planning the procedure. The data of each patient could be successfully postprocessed and used to map different resting state networks alongside the default mode network. On the basis of this study, it is feasible to use the information obtained from perfusion imaging to visualize not only vascular signal but also functional activation of resting state networks without acquiring any additional data besides the already available information. This may help guide the neurosurgeon in real time to adjust the surgical plan.
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http://dx.doi.org/10.1016/j.wneu.2021.10.107DOI Listing
January 2022

Current Applications and Future Development of Magnetic Resonance Fingerprinting in Diagnosis, Characterization, and Response Monitoring in Cancer.

Cancers (Basel) 2021 Sep 22;13(19). Epub 2021 Sep 22.

High Dimensional Neurology Group, Queen's Square Institute of Neurology, University College London, London WC1N 3BG, UK.

Magnetic resonance imaging (MRI) has enabled non-invasive cancer diagnosis, monitoring, and management in common clinical settings. However, inadequate quantitative analyses in MRI continue to limit its full potential and these often have an impact on clinicians' judgments. Magnetic resonance fingerprinting (MRF) has recently been introduced to acquire multiple quantitative parameters simultaneously in a reasonable timeframe. Initial retrospective studies have demonstrated the feasibility of using MRF for various cancer characterizations. Further trials with larger cohorts are still needed to explore the repeatability and reproducibility of the data acquired by MRF. At the moment, technical difficulties such as undesirable processing time or lack of motion robustness are limiting further implementations of MRF in clinical oncology. This review summarises the latest findings and technology developments for the use of MRF in cancer management and suggests possible future implications of MRF in characterizing tumour heterogeneity and response assessment.
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http://dx.doi.org/10.3390/cancers13194742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507535PMC
September 2021

Cost-effectiveness of a quality improvement project, including simulation-based training, on reducing door-to-needle times in stroke thrombolysis.

BMJ Qual Saf 2021 Oct 1. Epub 2021 Oct 1.

Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.

Background: Rapid revascularisation in acute ischaemic stroke is crucial to reduce its total burden including societal costs. A quality improvement (QI) project that included streamlining the stroke care pathway and simulation-based training was followed by a significant reduction in median door-to-needle time (27 to 13 min) and improved patient outcomes after stroke thrombolysis at our centre. Here, we present a retrospective cost-effectiveness analysis of the QI project.

Methods: Costs for implementing and sustaining QI were assessed using recognised frameworks for economic evaluations. Effectiveness was calculated from previously published outcome measures. Cost-effectiveness was presented as incremental cost-effectiveness ratios including costs per minute door-to-needle time reduction per patient, and costs per averted death in the 13-month post-intervention period. We also estimated incremental cost-effectiveness ratios for a projected 5-year post-intervention period and for varying numbers of patients treated with thrombolysis. Furthermore, we performed a sensitivity analysis including and excluding costs of unpaid time.

Results: All costs including fixed costs for implementing the QI project totalled US$44 802, while monthly costs were US$2141. We calculated a mean reduction in door-to-needle time of 13.1 min per patient and 6.36 annual averted deaths. Across different scenarios, the estimated costs per minute reduction in door-to-needle time per patient ranged from US$13 to US$29, and the estimated costs per averted death ranged from US$4679 to US$10 543.

Conclusions: We have shown that a QI project aiming to improve stroke thrombolysis treatment at our centre can be implemented and sustained at a relatively low cost with increasing cost-effectiveness over time. Our work builds on the emerging theory and practice for economic evaluations in QI projects and simulation-based training. The presented cost-effectiveness data might help guide healthcare leaders planning similar interventions.
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http://dx.doi.org/10.1136/bmjqs-2021-013398DOI Listing
October 2021

One-pot and one-step automated radio-synthesis of [F]AlF-FAPI-74 using a multi purpose synthesizer: a proof-of-concept experiment.

EJNMMI Radiopharm Chem 2021 Aug 21;6(1):28. Epub 2021 Aug 21.

Department for Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.

Background: Fibroblast activation protein (FAP) is overexpressed in the stroma of many types of cancer. [F]AlF-FAPI-74 is a positron emission tomography tracer with high selectivity for FAP, which has already shown high accumulation within human tumors in clinical studies. However, [F]AlF-FAPI-74 radiosynthesis has not been optimized using an automated synthesizer. Herein, we report a one-pot and one-step automated radiosynthesis method using a multi purpose synthesizer.

Results: Radiosynthesis of [F]AlF-FAPI-74 was performed using a cassette-type multi purpose synthesizer CFN-MPS200. After the recovery rate of trapped [F]fluoride onto the anion-exchange cartridge using a small amount of eluent was investigated manually, a dedicated [F]AlF-FAPI-74 synthesis cassette and synthesis program for one-pot and one-step fluorination was developed. The solutions for the formulation of [F]AlF-FAPI-74 synthesized using this were evaluated to obtain stable radiochemical purity. The recovery rate of [F]fluoride with only 300 µL of eluent ranged 90 ± 9% by introduction from the male side and elution from the female side of the cartridge. In automated synthesis, the eluted [F]fluoride and precursor solution containing aluminum chloride were mixed; then, fluorination was performed in a one-pot and one-step process at room temperature for 5 min, followed by 15 min at 95 °C. As a result, the radioactivity of [F]AlF-FAPI-74 was 11.3 ± 1.1 GBq at the end of synthesis from 32 to 40 GBq of [F]fluoride, and its radiochemical yield was 37 ± 4% (n = 10). The radiochemical purity at the end of the synthesis was ≥ 97% for all formulation solutions. When the diluent was saline, the radiochemical purity markedly decreased after 4 h of synthesis. In contrast, with phosphate-buffered saline (pH 7.4) or 10 mM phosphate-buffered saline (pH 6.7) containing 100 mg of sodium ascorbate, the radiochemical purity was stable at 97%. Non-radioactive AlF-FAPI-74 and total impurities, including non-radioactive AlF-FAPI-74, were 0.3 ± 0.1 µg/mL and 2.8 ± 0.6 µg/mL. Ethanol concentration and residual DMSO were 5.5 ± 0.2% and 21 ± 6 ppm, respectively.

Conclusions: We established a one-pot one-step automated synthesis method using a CFN-MPS200 synthesizer that provided high radioactivity and stable radiochemical purity for possible clinical applications.
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http://dx.doi.org/10.1186/s41181-021-00142-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380200PMC
August 2021

F-labeled tracers targeting fibroblast activation protein.

EJNMMI Radiopharm Chem 2021 Aug 21;6(1):26. Epub 2021 Aug 21.

Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Background: Cancer-associated fibroblasts are found in the stroma of epithelial tumors. They are characterized by overexpression of the fibroblast activation protein (FAP), a serine protease which was already proven as attractive target for chelator-based theranostics. Unfortunately, the value of gallium-68 labeled tracers is limited by their batch size and the short nuclide half-life. To overcome this drawback, radiolabeling with aluminum fluoride complexes and 6-fluoronicotinamide derivatives of the longer-lived nuclide fluorine-18 was established. The novel compounds were tested for their FAP-specific binding affinity. Uptake and binding competition were studied in vitro using FAP expressing HT-1080 cells. HEK cells transfected with the closely related dipeptidyl peptidase-4 (HEK-CD26) were used as negative control. Small animal positron emission tomography imaging and biodistribution experiments were performed in HT-1080-FAP xenografted nude mice. [F]AlF-FAPI-74 was selected for PET/CT imaging in a non-small cell lung cancer (NSCLC) patient.

Results: In vitro, F-labeled FAPI-derivatives demonstrated high affinity (EC = < 1 nm to 4.2 nm) and binding of up to 80% to the FAP-expressing HT1080 cells while no binding to HEK-CD26 cells was observed. While small animal PET imaging revealed unfavorable biliary excretion of most of the F-labeled compounds, the NOTA bearing compounds [F]AlF-FAPI-74 and -75 achieved good tumor-to-background ratios, as a result of their preferred renal excretion. These two compounds showed the highest tumor accumulation in PET imaging. The organ distribution values of [F]AlF-FAPI-74 were in accordance with the small animal PET imaging results. Due to its less complex synthesis, fast clearance and low background values, [F]AlF-FAPI-74 was chosen for clinical imaging. PET/CT of a patient with metastasized non-small cell lung cancer (NSCLC), enabled visualization of the primary tumor and its metastases at the hepatic portal and in several bones. This was accompanied by a rapid clearance from the blood pool and low background in healthy organs.

Conclusion: [F]AlF-labeled FAPI derivatives represent powerful tracers for PET. Owing to an excellent performance in PET imaging, FAPI-74 can be regarded as a promising precursor for [F]AlF-based FAP-imaging.
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http://dx.doi.org/10.1186/s41181-021-00144-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380212PMC
August 2021

Two Tumors, One Target: Preliminary Experience With 90Y-FAPI Therapy in a Patient With Metastasized Breast and Colorectal Cancer.

Clin Nucl Med 2021 Oct;46(10):842-844

From the Department of Nuclear Medicine, Heidelberg University Hospital.

Abstract: We report a patient with breast cancer (BC) diagnosed in 2009 with metachronous lymph node, liver, and bone metastases. In 2017, colorectal cancer with peritoneal metastases was additionally diagnosed and treated with 8 cycles of capecitabine due to its antitumor activity against both malignancies. At progression of both diseases, FAPI PET/CT demonstrated positive tumor targeting in BC-related metastases and colorectal cancer-related metastases. The patient received an experimental therapy with 90Y-FAPI46. Although there was similar tracer uptake in the PET/CT, the radioligand therapy resulted in mixed response with disappearance of peritoneal metastases but minor efficacy treating the BC-related metastases.
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http://dx.doi.org/10.1097/RLU.0000000000003842DOI Listing
October 2021

Value of Dual-Energy Dual-Layer CT After Mechanical Recanalization for the Quantification of Ischemic Brain Edema.

Front Neurol 2021 19;12:668030. Epub 2021 Jul 19.

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Ischemic brain edema can be measured in computed tomography (CT) using quantitative net water uptake (NWU), a recently established imaging biomarker. NWU determined in follow-up CT after mechanical thrombectomy (MT) has shown to be a strong predictor of functional outcome. However, disruption of the blood-brain barrier after MT may also lead to contrast staining, increasing the density on CT scans, and hence, directly impairing measurements of NWU. The purpose of this study was to determine whether dual-energy dual-layer CT (DDCT) after MT can improve the quantification of NWU by measuring NWU in conventional polychromatic CT images (CP-I) and virtual non-contrast images (VNC-I). We hypothesized that VNC-based NWU (vNWU) differs from NWU in conventional CT (cNWU). Ten patients with middle cerebral artery occlusion who received a DDCT follow-up scan after MT were included. NWU was quantified in conventional and VNC images as previously published and was compared using paired sample -tests. The mean cNWU was 3.3% (95%CI: 0-0.41%), and vNWU was 11% (95%CI: 1.3-23.4), which was not statistically different ( = 0.09). Two patients showed significant differences between cNWU and vNWU (Δ = 24% and Δ = 36%), while the agreement of cNWU/vNWU in 8/10 patients was high (difference 2.3%, = 0.23). NWU may be quantified precisely on conventional CT images, as the underestimation of ischemic edema due to contrast staining was low. However, a proportion of patients after MT might show significant contrast leakage resulting in edema underestimation. Further research is needed to validate these findings and investigate clinical implications.
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http://dx.doi.org/10.3389/fneur.2021.668030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326321PMC
July 2021

Value of Perfusion CT in the Prediction of Intracerebral Hemorrhage after Endovascular Treatment.

Stroke Res Treat 2021 22;2021:9933015. Epub 2021 Jul 22.

Department for Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Intracerebral hemorrhage (ICH) is a serious complication of endovascular treatment (EVT) in stroke patients with large vessel occlusion (LVO) and associated with increased morbidity and mortality.

Aims: Identification of radiological predictors is highly relevant. We investigated the predictive power of computed tomography perfusion (CTP) parameters concerning ICH in patients receiving EVT.

Methods: 392 patients with anterior circulation LVO with multimodal CT imaging who underwent EVT were analyzed. CTP parameters were visually evaluated for modified ASPECTS regions and compared between patients without ICH, those with hemorrhagic infarction (HI), and those with parenchymal hematoma (PH) according to the ECASS criteria at follow-up imaging and broken down by ASPECTS regions.

Results: 168 received intravenous thrombolysis (IV-rtPA), and 115 developed subsequent ICH (29.3%), of which 74 were classified as HI and 41 as PH. Patients with HI and PH had lower ASPECTS than patients without ICH and worse functional outcome after 90 days ( < 0.05). In 102 of the 115 patients with ICH, the deep middle cerebral artery (MCA) territory was affected with differences between patients without ICH, those with HI, and those with PH regarding cerebral blood volume (CBV) and blood-brain barrier permeability measured as flow extraction product (FED) relative to the contralateral hemisphere ( < 0.05). Patients with PH showed larger perfusion CT infarct core than patients without ICH ( < 0.01).

Conclusion: None of the examined CTP parameters was found to be a strong predictor of subsequent ICH. ASPECTS and initial CTP core volume were more reliable and may be useful and even so more practicable to assess the risk of subsequent ICH after EVT.
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http://dx.doi.org/10.1155/2021/9933015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321751PMC
July 2021

Head-to-head intra-individual comparison of biodistribution and tumor uptake of Ga-FAPI and F-FDG PET/CT in cancer patients.

Eur J Nucl Med Mol Imaging 2021 12 17;48(13):4377-4385. Epub 2021 Jun 17.

Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.

Purpose: FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of Ga-FAPI versus standard-of-care F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers.

Material And Methods: This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both Ga-FAPI and F-FDG PET/CT within a median time interval of 10 days (range 1-89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ).

Results: A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. Ga-FAPI uptake in primary tumors and metastases was comparable to F-FDG in most cases. The SUVmax was significantly lower for Ga-FAPI than F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, Ga-FAPI TBRs were significantly higher than F-FDG TBRs in some sites, including liver and bone metastases.

Conclusion: Quantitative tumor uptake is comparable between Ga-FAPI and F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for Ga-FAPI. Thus, Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological F-FDG uptake.
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http://dx.doi.org/10.1007/s00259-021-05307-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566651PMC
December 2021

Virtual non-contrast enhanced magnetic resonance imaging (VNC-MRI).

Magn Reson Imaging 2021 09 11;81:67-74. Epub 2021 Jun 11.

Department of Diagnostic and Interventional Neuroradiology, University Hospital Hamburg-Eppendorf, Building W14, Martinistr. 52, 20251 Hamburg, Germany.

Purpose: Application of contrast agents (CA) is widely used in various clinical fields like oncology. Similar to approaches used in computed tomography, virtual non-contrast enhanced (VNC) images can be generated with the goal to supersede true non-contrast enhanced (TNC) images.

Methods: In MRI a T1-mapping sequence with variable flip angle (VFA) was used to acquire two images with different image contrast at the same time. To generate VNC images postprocessing based on this technique, an image-space based material decomposition algorithm was used. The inverse of a sensitivity matrix, consisting of intensity values for both VFA images and every material respectively, was used to determine the three material fractions and to calculate the final VNC images. The technique was tested on a 3 T scanner using a phantom and two in-vivo scans of patients with glioma and glioblastoma respectively. In all these cases the required six values were manually derived from the respective material or the background from both VFA images.

Results: Postprocessing results of the phantom show that the chosen materials can be separated and visualized individually and unwanted materials can be suppressed. In the VNC images of in-vivo scans the signal of the CA is removed successfully.

Conclusion: It was shown that VNC images that match the visual impression of the TNC images can be generated, resulting in possibly reduced scan times and avoided mismatches due to movement of the patient.
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http://dx.doi.org/10.1016/j.mri.2021.06.004DOI Listing
September 2021

Impact of intravenous alteplase on sub-angiographic emboli in high-resolution diffusion-weighted imaging following successful thrombectomy.

Eur Radiol 2021 Nov 8;31(11):8228-8235. Epub 2021 May 8.

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Objective: Thrombus microfragmentation causing peripheral emboli (PE) during mechanical thrombectomy (MT) may modulate treatment effects, even in cases with successful reperfusion. This study aims to investigate whether intravenous alteplase is of potential benefit in reducing PE after successful MT.

Methods: Patients from a prospective study treated at a tertiary care stroke center between 08/2017 and 12/2019 were analyzed. The main inclusion criterion was successful reperfusion after MT (defined as expanded thrombolysis in cerebral infarction (eTICI) scale ≥ 2b50) of large vessel occlusion anterior circulation stroke. All patients received a high-resolution diffusion-weighted imaging (DWI) follow-up 24 h after MT for PE detection. Patients were grouped as "direct MT" (no alteplase) or as MT plus additional intravenous alteplase. The number and volume of ischemic core lesions and PE were then quantified and analyzed.

Results: Fifty-six patients were prospectively enrolled. Additional intravenous alteplase was administered in 46.3% (26/56). There were no statistically significant differences of PE compared by groups of direct MT and additional intravenous alteplase administration regarding mean numbers (12.1, 95% CI 8.6-15.5 vs. 11.1, 95% CI 7.0-15.1; p = 0.701), and median volume (0.70 mL, IQR 0.21-1.55 vs. 0.39 mL, IQR 0.10-1.62; p = 0.554). In uni- and multivariable linear regression analysis, higher eTICI scores were significantly associated with reduced PE, while the administration of alteplase was neither associated with numbers nor volume of peripheral emboli. Additional alteplase did not alter reperfusion success.

Conclusions: Intravenous alteplase neither affects the number nor volume of sub-angiographic DWI-PE after successful endovascular reperfusion. In the light of currently running randomized trials, further studies are warranted to validate these findings.

Key Points: • Thrombus microfragmentation during endovascular stroke treatment may cause peripheral emboli that are only detectable on diffusion-weighted imaging and may directly compromise treatment effects. • In this prospective study, the application of intravenous alteplase did not influence the occurrence of peripheral emboli detected on high-resolution diffusion-weighted imaging. • A higher degree of recanalization was associated with a reduced number and volume of peripheral emboli and better functional outcome, while contrariwise, peripheral emboli did not modify the effect of recanalization on modified Rankin Scale scores at day 90.
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http://dx.doi.org/10.1007/s00330-021-07980-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523452PMC
November 2021

Nickel-Aluminum Thermal Spray Coatings as Adhesion Promoter and Susceptor for Inductively Joined Polymer-Metal Hybrids.

Polymers (Basel) 2021 Apr 17;13(8). Epub 2021 Apr 17.

Materials and Surface Engineering Group, Faculty of Mechanical Engineering, Chemnitz University of Technology, Erfenschlager Straße 73, D-09125 Chemnitz, Germany.

Hybrid joints of metal- and fiber-reinforced-polymer offer great potential for lightweight applications. Thereby, a fast and reliable joining process is mandatory for mass-production applications. To this end, this study assesses inductive spot-joining in combination with prior thermal spray coating of the metal adherent. A nickel-aluminum 95/5 coating was applied to achieve high adhesion through mechanical interlocking and to act as susceptor for the inductive joining process. The joint strength was assessed with lap shear specimens consisting of EN AW-6082 aluminum alloy and glass fiber reinforced polyamide 6 or polypropylene, respectively. The joints were further investigated in terms of heating time and hygrothermal cyclic loading. The results showed that significant time savings for the joining process as well as strong adhesion were achieved due to the coating. Moreover, the high strengths were even preserved under hygrothermal cyclic loading.
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http://dx.doi.org/10.3390/polym13081320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072882PMC
April 2021

[Sm]Samarium-labeled FAPI-46 radioligand therapy in a patient with lung metastases of a sarcoma.

Eur J Nucl Med Mol Imaging 2021 08 17;48(9):3011-3013. Epub 2021 Mar 17.

Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120, Heidelberg, Germany.

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http://dx.doi.org/10.1007/s00259-021-05273-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263436PMC
August 2021

3D-printed, patient-specific intracranial aneurysm models: From clinical data to flow experiments with endovascular devices.

Med Phys 2021 Apr 17;48(4):1469-1484. Epub 2021 Feb 17.

Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Kiel, Germany.

Purpose: Flow models of intracranial aneurysms (IAs) can be used to test new and existing endovascular treatments with flow modulation devices (FMDs). Additionally, 4D flow magnetic resonance imaging (MRI) offers the ability to measure hemodynamics. This way, the effect of FMDs can be determined noninvasively and compared to patient data. Here, we describe a cost-effective method for producing flow models to test the efficiency of FMDs with 4D flow MRI.

Methods: The models were based on human radiological data (internal carotid and basilar arteries) and printed in 3D with stereolithography. The models were printed with three different printing layers (25, 50, and 100 µm thickness). To evaluate the models in vitro, 3D rotational angiography, time-of-flight MRI, and 4D flow MRI were employed. The flow and geometry of one model were compared with in vivo data. Two FMDs (FMD1 and FMD2) were deployed into two different IA models, and the effect on the flow was estimated by 4D flow MRI.

Results: Models printed with different layer thicknesses exhibited similar flow and little geometric variation. The mean spatial difference between the vessel geometry measured in vivo and in vitro was 0.7 ± 1.1 mm. The main flow features, such as vortices in the IAs, were reproduced. The velocities in the aneurysms were similar in vivo and in vitro (mean velocity magnitude: 5.4 ± 7.6 and 7.7 ± 8.6 cm/s, maximum velocity magnitude: 72.5 and 55.1 cm/s). By deploying FMDs, the mean velocity was reduced in the IAs (from 8.3 ± 10 to 4.3 ± 9.32 cm/s for FMD1 and 9.9 ± 12.1 to 2.1 ± 5.6 cm/s for FMD2).

Conclusions: The presented method allows to produce neurovascular models in approx. 15 to 30 h. The resulting models were found to be geometrically accurate, reproducing the main flow patterns, and suitable for implanting FMDs as well as 4D flow MRI.
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http://dx.doi.org/10.1002/mp.14714DOI Listing
April 2021

Early Prediction of Malignant Cerebellar Edema in Posterior Circulation Stroke Using Quantitative Lesion Water Uptake.

Neurosurgery 2021 02;88(3):531-537

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Malignant cerebellar edema (MCE) is a life-threatening complication of ischemic posterior circulation stroke that requires timely diagnosis and management. Yet, there is no established imaging biomarker that may serve as predictor of MCE. Early edematous water uptake can be determined using quantitative lesion water uptake, but this biomarker has only been applied in anterior circulation strokes.

Objective: To test the hypothesis that lesion water uptake in early posterior circulation stroke predicts MCE.

Methods: A total 179 patients with posterior circulation stroke and multimodal admission CT were included. A total of 35 (19.5%) patients developed MCE defined by using an established 10-point scale in follow-up CT, of which ≥4 points are considered malignant. Posterior circulation net water uptake (pcNWU) was quantified in admission CT based on CT densitometry and compared with posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) as predictor of MCE using receiver operating curve (ROC) analysis and logistic regression analysis.

Results: Acute pcNWU within the early ischemic lesion was 24.6% (±8.4) for malignant and 7.2% (±7.4) for nonmalignant infarctions, respectively (P < .0001). Based on ROC analysis, pcNWU above 14.9% identified MCE with high discriminative power (area under the curve: 0.94; 95% CI: 0.89-0.97). Early pcNWU (odds ratio [OR]: 1.28; 95% CI: 1.15-1.42, P < .0001) and pc-ASPECTS (OR: 0.71, 95% CI: 0.53-0.95, P = .02) were associated with MCE, adjusted for age and recanalization status.

Conclusion: Quantitative pcNWU in early posterior circulation stroke is an important marker for MCE. Besides pc-ASPECTS, lesion water uptake measurements may further support identifying patients at risk for MCE at an early stage indicating stricter monitoring and consideration for further therapeutic measures.
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http://dx.doi.org/10.1093/neuros/nyaa438DOI Listing
February 2021

N-terminal pro-B-type natriuretic peptide as a prognostic indicator for 30-day mortality following out-of-hospital cardiac arrest: a prospective observational study.

BMC Cardiovasc Disord 2020 08 24;20(1):382. Epub 2020 Aug 24.

Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.

Background: Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA).

Methods: We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission.

Results: A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors (p <  0.001) and significantly associated with 30-days all-cause mortality in univariate analysis, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% confidence interval (CI), 2.1-10.1), p <  0.001. This association was no longer significant in multivariable analysis applying continuous values, [HR 0.96, (95% CI, 0.64-1.43), p = 0.84]. Similar results were obtained by dividing the population by survival at hospital admission, excluding non-return of spontaneous circulation (ROSC) patients on scene [HR 0.93 (95% CI, 0.50-1.73), P = 0.83]. We also noted that NT-proBNP was significantly higher in asystole- as compared to VF-patients, p <  0.001.

Conclusions: Early-on levels of hs-cTnT, copeptin and NT-proBNP did not provide independent prognostic information following OHCA. Prediction was unaffected by excluding on-scene non-ROSC patients in the multivariable analysis.

Trial Registration: ClinicalTrials. gov, NCT02886273 .
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http://dx.doi.org/10.1186/s12872-020-01630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445901PMC
August 2020

Cardiac arrest as a reportable condition: a cohort study of the first 6 years of the Norwegian out-of-hospital cardiac arrest registry.

BMJ Open 2020 07 8;10(7):e038133. Epub 2020 Jul 8.

Division of Prehospital Services, Oslo University Hospital, Oslo, Norway.

Objectives: The Norwegian Cardiac Arrest Registry (NorCAR) was established in 2013 when cardiac arrest became a mandatory reportable condition. The aim of this cohort study is to describe how the world's first mandatory, population-based cardiac arrest registry evolved during its first 6 years.

Setting: Norway has a total population of 5.3 million inhabitants with a population density that varies considerably. All residents are assigned a unique identifier number, giving nationally approved registries access to information about all births and deaths in the country. Data in the registry are entered by data processors; public employees with close links to the emergency medical services. All data processors undergo a standardised training and meet for yearly retraining and updates.

Participants: All events of cardiac arrest where bystanders or healthcare professionals have started cardiopulmonary resuscitation or performed defibrillation are included into the NorCAR.

Primary And Secondary Outcome Measures: Since the establishment of the registry, the number of reporting health trusts, the number of reported events and the corresponding population at risk were followed year by year. Outcome is measured as changes in inclusion rate, incidence per 100 000 inhabitants and survival to 30 days after cardiac arrest.

Results: In total, 14 849 cases were registered over 6 years, between 2013 and 2018. The number of health trusts reporting rose steadily from 2013. Within 3 years, all trusts reported to the registry with an increasing number of events reported; going from 1101 to 3400 per year. The prevalence of bystander cardiopulmonary resuscitation increased slightly, but the population incidence of survival did not change.

Conclusion: Declaring cardiac arrest as a reportable condition and close follow-up of all reporting areas is essential when building a national registry.
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http://dx.doi.org/10.1136/bmjopen-2020-038133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348469PMC
July 2020

FAPI-74 PET/CT Using Either F-AlF or Cold-Kit Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients.

J Nucl Med 2021 02 26;62(2):201-207. Epub 2020 Jun 26.

Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of Ga (68 min) creates problems with manufacture and delivery. F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both F-AlF and Ga. Here, we describe the in vivo evaluation of F-FAPI-74 and a proof of mechanism for Ga-FAPI-74 labeled at ambient temperature. In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of Ga-FAPI-74. The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUV of more than 10. The effective dose per a 100-MBq administered activity of F-FAPI-74 was 1.4 ± 0.2 mSv, and for Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic F-FAPI-74 PET scan is even lower than that of PET scans with F-FDG and other F tracers; Ga-FAPI-74 is comparable to other Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy. The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of F-FAPI-74 or decentralized cold-kit labeling of Ga-FAPI-74 allows flexible routine use.
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http://dx.doi.org/10.2967/jnumed.120.245084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8679591PMC
February 2021

Introducing Fractal Dimension for Interlaminar Shear and Tensile Strength Assessment of Mechanically Interlocked Polymer-Metal Interfaces.

Materials (Basel) 2020 May 8;13(9). Epub 2020 May 8.

Materials and Surface Engineering Group, Faculty of Mechanical Engineering, Chemnitz University of Technology, Erfenschlager Straße 73, D-09125 Chemnitz, Germany.

The interlaminar strength of mechanically interlocked polymer-metal interfaces is strongly dependent on the surface structure of the metal component. Therefore, this contribution assesses the suitability of the fractal dimension for quantification of the surface structure, as well as interlaminar strength prediction of aluminum/polyamide 6 polymer-metal hybrids. Seven different surface structures, manufactured by mechanical blasting, combined mechanical blasting and etching, thermal spraying, and laser ablation, are investigated. The experiments are carried out on a butt-bonded hollow cylinder testing method that allows shear and tensile strength determination with one specific specimen geometry. The fractal dimension of the metal surfaces is derived from cross-sectional images. For comparison, the surface roughness slope is determined and related to the interlaminar strength. Finally, a fracture analysis is conducted. For the investigated material combination, the experimental results indicate that the fractal dimension is an appropriate measure for predicting the interlaminar strength.
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http://dx.doi.org/10.3390/ma13092171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254221PMC
May 2020

FAP-specific PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype glioblastomas.

Eur J Radiol 2020 Jun 20;127:109021. Epub 2020 Apr 20.

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Objectives: Targeting Fibroblast Activation Protein (FAP) is a new approach for glioblastoma imaging. In a recent pilot study glioblastomas showed elevated tracer uptake with high intratumoral heterogeneity in projection on the corresponding T2w/FLAIR and contrast enhanced MRI lesions. In this study, we correlated FAP-specific signaling with apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) signals in MRI to further characterize the significance of FAP uptake.

Methods: Clinical PET/CT scans of 13 glioblastoma patients were performed post i. v. administration of Ga-labelled-FAP-specific tracer molecules. PET- and corresponding MRI-scans were co-registrated. 3d volumetric segmentations were performed of T2w/FLAIR lesions and contrast enhancing lesions within co-registrated MRI slides. Signal intensity values of FAP-specific PET signaling, ADC and rCBV were analyzed for their pixel wise correlation in each patient. Pooled estimates of the correlation coefficients were calculated by using the Fisher z-transformation.

Results: FAP-specific PET signals showed a moderately positive correlation with rCBV values which is more pronounced within the T2w/FLAIR lesion (pooled correlation 0,229) than in the contrast enhancing tumor region (pooled correlation 0.09). FAP-specific PET signals showed no correlation with ADC values.

Conclusions: The moderately positive correlation of FAP-specific signals with rCBV values in MRI indicates that FAP-signaling is not independent from perfusion, but also does not only reflect intratumoral perfusion differences. The missing correlation of FAP-specific signals with ADC indicates that FAP-specific imaging does not reflect cell density, but the spot-like expression of FAP in glioblastomas. The clinical value of FAP-specific imaging needs further investigation.
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http://dx.doi.org/10.1016/j.ejrad.2020.109021DOI Listing
June 2020

Design and Development of Tc-Labeled FAPI Tracers for SPECT Imaging and Re Therapy.

J Nucl Med 2020 10 13;61(10):1507-1513. Epub 2020 Mar 13.

Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg Germany

Most epithelial tumors recruit fibroblasts and other nonmalignant cells and activate them into cancer-associated fibroblasts. This often leads to overexpression of the membrane serine protease fibroblast-activating protein (FAP). It has already been shown that DOTA-bearing FAP inhibitors (FAPIs) generate high-contrast images with PET/CT scans. Since SPECT is a lower-cost and more widely available alternative to PET, Tc-labeled FAPIs represent attractive tracers for imaging applications in a larger number of patients. Furthermore, the chemically homologous nuclide Re is available from generators, which allows FAP-targeted endoradiotherapy. For the preparation of Tc-tricarbonyl complexes, a chelator was selected whose carboxylic acids can easily be converted into various derivatives in the finished product, enabling a platform strategy based on the original tracer. The obtained Tc complexes were investigated in vitro by binding and competition experiments on FAP-transfected HT-1080 (HT-1080-FAP) or on mouse FAP-expressing (HEK-muFAP) and CD26-expressing (HEKCD26) HEK cells and characterized by planar scintigraphy and organ distribution studies in tumor-bearing mice. Furthermore, a first-in-humans application was done on 2 patients with ovarian and pancreatic cancer, respectively. Tc-FAPI-19 showed specific binding to recombinant FAP-expressing cells with high affinity. Unfortunately, liver accumulation, biliary excretion, and no tumor uptake were observed on planar scintigraphy for a HT-1080-FAP-xenotransplanted mouse. To improve the pharmacokinetic properties, hydrophilic amino acids were attached to the chelator moiety of the compound. The resulting Tc-labeled FAPI tracers revealed excellent binding properties (≤45% binding; >95% internalization), high affinity (half-maximal inhibitory concentration, 6.4-12.7 nM), and significant tumor uptake (≤5.4% injected dose per gram of tissue) in biodistribution studies. The lead candidate Tc-FAPI-34 was applied for diagnostic scintigraphy and SPECT of patients with metastasized ovarian and pancreatic cancer for follow-up to therapy with Y-FAPI-46. Tc-FAPI-34 accumulated in the tumor lesions, as also shown on PET/CT imaging using Ga-FAPI-46. Tc-FAPI-34 represents a powerful tracer for diagnostic scintigraphy, especially when PET imaging is not available. Additionally, the chelator used in this compound allows labeling with the therapeutic nuclide Re, which is planned for the near future.
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http://dx.doi.org/10.2967/jnumed.119.239731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539653PMC
October 2020

Ternary encoded super-selective arterial spin labeling for time-resolved flow territory mapping.

Phys Med Biol 2020 05 11;65(10):10NT01. Epub 2020 May 11.

Department of Radiology and Neuroradiology, UKSH Campus Kiel, Kiel, Germany. Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Arterial spin labeling (ASL) is a non-contrast enhanced method for perfusion measurements. The obtained information is in general a snap-shot of the whole-brain perfusion. Image acquisition is performed after a certain delay time after the labeling of the arterial blood. Time-resolved information alongside flow territory mapping of individual arteries can become useful for the collection of important information such as arterial crossflow, and revascularization. Therefore, a method is presented that combines time-resolved flow territory mapping within a single scan based on encoding of the acquisition cycle using a ternary matrix approach. The super-selective tagging process is divided in individual blocks following a ternary matrix encoding scheme. In each block, the position of the labeling focus changes its position to each of the major brain feeding arteries. Contrary to conventional ASL approaches, no control condition is acquired and the individual flow territories are calculated by combining the label images only. The method was successfully evaluated in healthy volunteers. Each flow territory could be visualized over several post labeling delays within a single scan of approximately five minutes. Comparison of signal intensity (relative perfusion) did not show statistically significant differences between the methods. Encoding super-selective ASL using a ternary matrix allows for the vessel-selective and time-resolved acquisition of perfusion territories within a single scan.
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http://dx.doi.org/10.1088/1361-6560/ab7ef0DOI Listing
May 2020

The Role of Ga-FAPI PET/CT for Patients with Malignancies of the Lower Gastrointestinal Tract: First Clinical Experience.

J Nucl Med 2020 09 14;61(9):1331-1336. Epub 2020 Feb 14.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

For oncologic management or radiotherapy planning, reliable staging tools are essential. The recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitor (FAPI) PET/CT as a first clinical analysis for primary malignancies within the lower gastrointestinal tract (LGT). Ga-FAPI PET/CT was performed on a cohort of 22 patients with LGT tumors, including 15 patients with metastatic disease, 1 patient with suspected local relapse, and 6 treatment-naïve patients. Uptake of Ga-FAPI-04 and Ga-FAPI-46 was quantified by SUV and SUV After comparison with standard imaging, changes in tumor stage or localization and in oncologic or radiooncologic management were recorded. The highest uptake of FAPI tracer was observed in liver metastases and anal cancer, with an SUV of 9.1 and 13.9, respectively. Because of low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50%, whereas in patients with metastases, new findings occurred in 47%. In total, FAPI imaging caused a high, medium, and low change in oncologic or radiooncologic management in 19%, 33%, and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by Ga-FAPI PET/CT. The present study demonstrated that both primary and metastatic LGT tumors were reliably detected by Ga-FAPI PET/CT, leading to relevant changes in TNM status and oncologic or radiooncologic management. Ga-FAPI PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT tumors, potentially opening new applications for tumor staging or restaging.
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http://dx.doi.org/10.2967/jnumed.119.237016DOI Listing
September 2020

Radiation Dosimetry and Biodistribution of Ga-FAPI-46 PET Imaging in Cancer Patients.

J Nucl Med 2020 08 13;61(8):1171-1177. Epub 2019 Dec 13.

Physics and Biology in Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, UCLA, Los Angeles, California

Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of Ga-FAPI-46 in cancer patients. Six patients with different cancers underwent serial Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUV/organ SUV). At all time points, average SUV was highest in the liver. Tumor and organ SUV decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04 mSv/MBq). The average effective total-body dose was 7.80E-03 mSv/MBq. Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.
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http://dx.doi.org/10.2967/jnumed.119.236786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413240PMC
August 2020

Segmentation-Based Blood Flow Parameter Refinement in Cerebrovascular Structures Using 4-D Arterial Spin Labeling MRA.

IEEE Trans Biomed Eng 2020 07 1;67(7):1936-1946. Epub 2019 Nov 1.

Objective: Cerebrovascular diseases are one of the main global causes of death and disability in the adult population. The preferred imaging modality for the diagnostic routine is digital subtraction angiography, an invasive modality. Time-resolved three-dimensional arterial spin labeling magnetic resonance angiography (4D ASL MRA) is an alternative non-invasive modality, which captures morphological and blood flow data of the cerebrovascular system, with high spatial and temporal resolution. This work proposes advanced medical image processing methods that extract the anatomical and hemodynamic information contained in 4D ASL MRA datasets.

Methods: A previously published segmentation method, which uses blood flow data to improve its accuracy, is extended to estimate blood flow parameters by fitting a mathematical model to the measured vascular signal. The estimated values are then refined using regression techniques within the cerebrovascular segmentation. The proposed method was evaluated using fifteen 4D ASL MRA phantoms, with ground-truth morphological and hemodynamic data, fifteen 4D ASL MRA datasets acquired from healthy volunteers, and two 4D ASL MRA datasets from patients with a stenosis.

Results: The proposed method reached an average Dice similarity coefficient of 0.957 and 0.938 in the phantom and real dataset segmentation evaluations, respectively. The estimated blood flow parameter values are more similar to the ground-truth values after the refinement step, when using phantoms. A qualitative analysis showed that the refined blood flow estimation is more realistic compared to the raw hemodynamic parameters.

Conclusion: The proposed method can provide accurate segmentations and blood flow parameter estimations in the cerebrovascular system using 4D ASL MRA datasets.

Significance: The information obtained with the proposed method can help clinicians and researchers to study the cerebrovascular system non-invasively.
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http://dx.doi.org/10.1109/TBME.2019.2951082DOI Listing
July 2020

Targeting of activated fibroblasts for imaging and therapy.

EJNMMI Radiopharm Chem 2019 Jul 25;4(1):16. Epub 2019 Jul 25.

Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Tumors form a complex environment consisting of a variety of non-malignant cells. Especially cancer-associated fibroblasts have been shown to have an important role for different aspects of malignant tumors such as migration, metastasis, resistance to chemotherapy and immunosuppression. Therefore, a targeting of these cells may be useful for both imaging and therapy. In this respect, an interesting target is the fibroblast activation protein (FAP) which is expressed in activated fibroblasts, but not in quiescent fibroblasts, giving the opportunity to use this membrane-anchored enzyme as a target for radionuclide-based approaches for diagnosis and treatment of tumors and for the diagnosis of non-malignant disease associated with a remodelling of the extracellular matrix.
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http://dx.doi.org/10.1186/s41181-019-0069-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658625PMC
July 2019

Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: Cu- and Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models.

J Nucl Med 2020 04 4;61(4):563-569. Epub 2019 Oct 4.

Institute for Radiation Sciences, Osaka University, Osaka, Japan.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, Cu (half-life, 12.7 h) and Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, = 12; MIA PaCa-2, = 8). Tumor xenograft mice were investigated after the intravenous injection of Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice ( = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice ( = 6). Tumor size was monitored and compared with that of control mice ( = 6). Dynamic imaging of Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for Cu-FAPI-04 than for Ga-FAPI-04, except in the heart, and excretion in the urine was higher for Ga-FAPI-04 than for Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. This proof-of-concept study showed that Cu-FAPI-04 and Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.
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http://dx.doi.org/10.2967/jnumed.119.233122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198371PMC
April 2020

Effect of Metal Surface Topography on the Interlaminar Shear and Tensile Strength of Aluminum/Polyamide 6 Polymer-Metal-Hybrids.

Materials (Basel) 2019 Sep 12;12(18). Epub 2019 Sep 12.

Materials and Surface Engineering Group, Faculty of Mechanical Engineering, Chemnitz University of Technology, D-09107 Chemnitz, Germany.

Mechanical interlocking has been proven to be an effective bonding mechanism for dissimilar material groups like polymers and metals. Therefore, this contribution assesses several surface pretreatments for the metallic adherent. Blasting, etching, combined blasting and etching, thermal spraying, and laser structuring processes are investigated with regard to the achievable interlaminar strength and the corresponding surface roughness parameters. The experiments are carried out on EN AW-6082/polyamide 6 polymer-metal-hybrids, utilizing a novel butt-bonded hollow cylinder specimen geometry for determining the shear and tensile strength. The experimental results indicate that the surface roughness slope has a major impact on the interlaminar strength. A laser-generated pin structure is found to provide the best mechanical performance as well as the highest surface slope of all investigated structuring methods.
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http://dx.doi.org/10.3390/ma12182963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766192PMC
September 2019

Phenanthroline-Based Molecular Switches for Prospective Chemical Grafting: A Synthetic Strategy and Its Application to Spin-Crossover Complexes.

Inorg Chem 2020 Mar 11;59(5):2659-2666. Epub 2019 Sep 11.

Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Egerlandstraße 1, 91058 Erlangen, Germany.

1,10-Phenanthroline represents a well-known versatile ligand system finding many applications in chemistry, biology, and material science. The properties and thus the use of these molecules are determined by coordinating metal ions and ligand substituents. Advanced ligand systems that, for instance, feature simultaneously an integrated photochrome and a surface anchoring group require the introduction of several differing substituents and the synthesis of asymmetric derivatives. In spite of a long history of the ligand system-and to our great surprise-a general synthetic approach allowing the introduction of differing substituents at positions (3,8) and (5,6) of 1,10-phenanthroline is not known. Here, we present a general approach for the synthesis of such phenanthrolines. The approach is used to integrate a diarylethene photochrome into a functionalized phenanthroline and thus to synthesize a novel photoswitchable phenanthroline and a corresponding spin-crossover molecular photoswitch. The functionality of both the ligand and its iron(II) complex at room temperature has been demonstrated. The importance of this work for chemical grafting of molecular switches based on phenanthrolines is emphasized.
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http://dx.doi.org/10.1021/acs.inorgchem.9b01424DOI Listing
March 2020
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