Direkter Vergleich der Peptid Rezeptor Radionuklidtherapie an Neuroendokrinen Neoplasien mit 177Lu-DOTATOC und 177Lu-DOTA-JR11 im Kleintiermodell mittels multimodaler Bildgebung

Einleitung: Neuroendokrine Neoplasien (NEN) sind seltene Tumorerkrankungen, die häufig erst in einem fortgeschrittenen Tumorstadium diagnostiziert werden. Die Peptid Rezeptor Radionuklidtherapie (PRRT) unter Verwendung von radioaktiv markierten Somatostatinrezeptor (SSTR) Agonisten stellt eine gängige und effektive palliative Therapieoption dar. Seit 2006 stehen vielversprechende SSTR Antagonisten im Fokus der Forschung. In der aktuellen Studie haben wir in einem orthotopen Mausmodell die PRRT mit zwei Zyklen des neuen SSTR Antagonisten 177Lu-DOTA-JR11 mit dem gängigen Agonisten 177Lu-DOTATOC mittels multimodaler morphologischer und funktioneller Bildgebung verglichen. Methoden: In vitro Bindungs- und Internalisierungsassays sowie eine Zellzyklusanalyse wurden durchgeführt. Für die in vivo Versuche wurde ein orthotopes Mausmodell einer pankreatischen NEN mit SSTR2 transfizierten BON-Zellen verwendet. Nach einer initialen Aktivitätsstudie (n = 12), erhielten die Tiere zwei Therapiezyklen im Abstand von drei Wochen mit jeweils entweder 100 µl Kochsalzlösung (n = 4), 20 MBq 177Lu-DOTA-JR11 (n = 4) oder 30 MBq 177Lu-DOTATOC (n = 4) intravenös. Das Monitoring von Tumorgröße und Morphologie erfolgte wöchentlich mittels MRT, eine einmalige Kontrolle des Tumormetabolismus nach Abschluss der Therapie mittels FDG-PET/MRT. Der SSTR-Besatz sowie der Uptake der Radiopharmaka in Tumor und Nieren wurde mittels SPECT/CT untersucht. Ergebnisse: 177Lu-DOTA-JR11 zeigte in vitro eine 6-fach höhere Affinität verglichen mit dem Agonisten. In vivo präsentierte der SSTR Antagonist einen 4 – 6-fach höheren Tumoruptake sowie einen 3-fach höheren Tumor-to-Kidney Quotienten, verglichen mit 177Lu-DOTATOC. Während 177Lu-DOTA-JR11 ein über beide Therapiezyklen hin konstanter Uptake zeigte, kam es bei 177Lu-DOTATOC bei der zweiten Injektion zu einer signifikanten Abnahme (p = 0,01). Nach Therapie mit 177Lu-DOTA-JR11 kam es zu einer Reduktion der Tumorgröße (p < 0,001) sowie zu einem deutlich verlängerten medianen Überleben (207 d (IQR = 132 – 228)) gegenüber dem Agonisten (126 d (IQR = 118 – 129)). MRT gestützte Analysen der Tumormorphologie zeigten ausgeprägtere Nekroseareale in den 177Lu-DOTA-JR11 therapierten Tieren. Die FDG-PET/MRT nach Abschluss der Therapie erbrachte ein deutlich geringeres vitales Tumorvolumen für den SSTR Antagonisten (6,2 % (IQR = 2 – 23)) verglichen mit 177Lu-DOTATOC (24,1 % (IQR = 16 – 40)). Schlussfolgerung: Das verwendete multimodale Bildgebungsprotokoll erlaubt eine detaillierte Therapievalidierung mit Berücksichtigung von Tumormorphologie und Metabolismus. Der neue SSTR Antagonist 177Lu-DOTA-JR11 zeigt einen deutlich ausgeprägteren zytotoxischen Effekt in vitro wie auch in vivo sowie eine vorteilhafte Tumor-zu-Nieren Ratio.Neuroendocrine neoplasms (NEN) are rare tumors and often diagnosed at late stages with no curative therapy options. Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) agonists, is an approved and effective treatment regimen. Since 2006 new SSTR antagonists have been discussed to surpass agonists for PRRT. In this study, we compared a two-cycle antagonist-based PRRT (177Lu-DOTA-JR11) with the commonly used agonist 177Lu-DOTATOC in an orthotopic murine model. In addition to tumor size, functional parameters such as metabolism and SSTR state were evaluated using a multimodal imaging concept. Methods: First, in vitro analysis including binding, internalization assays and cell cycle analysis was performed. Next, we established an orthotopic murine model using the SSTR2 transfected pancreatic NEN cell line BON (BON-SSTR2). After an initial study to evaluate optimal activity and time interval (n = 12), a PRRT including two therapy cycles with an interval of three weeks was applied. Animals received intravenous injections of either 100 μl saline (n = 4), 20 MBq 177Lu-DOTA-JR11 (n = 4) or 30 MBq 177Lu-DOTATOC (n = 4). MRI was performed on a weekly basis for assessment of tumor volume and morphology. An FDG-PET/MRI scan after PRRT allowed quantification of metabolically active tumor tissue. SSTR levels and tumor and kidney uptake of the respective radiopharmaceuticals were evaluated using SPECT/CT. Results: 177Lu-DOTA-JR11 showed a 6-fold higher affinity compared to the agonist in vitro. In vivo, the SSTR antagonist presented a 4 – 6-fold higher tumor uptake and a 3-fold higher tumor-to-kidney ratio. 177Lu-DOTATOC showed a decreased tumor uptake during the second therapy cycle (p = 0.01), while 177Lu-DOTA-JR11 presented a stable or even increasing uptake. Treatment with the SSTR antagonist induced a significant reduction of tumor size (p < 0,001) and was associated with prolonged median survival (207 d (IQR = 132 – 228)) compared to the agonist (126 d (IQR = 118 – 129)). Visual assessment of the tumor morphology showed increasing fractions of intratumoral necrosis in 177Lu-DOTA-JR11 treated tumors. FDG-PET/MRI supported these results, showing less viable tumor tissue of only 6,2 % (IQR = 2 – 23) compared to 177Lu-DOTATOC (24,1 % (IQR = 16 – 40)). Conclusion: The applied multimodal imaging concept allowed a detailed analysis of the treatment effects including tumor morphology and metabolism, revealing a pronounced cytotoxic effect and a favorable tumor-to-kidney ratio of the new SSTR antagonist 177Lu-DOTA-JR11

Potentials of Deterministic Radio Propagation Simulation for AI-Enabled Localization and Sensing

Machine leaning (ML) and artificial intelligence (AI) enable new methods for localization and sensing in next-generation networks to fulfill a wide range of use cases. These approaches rely on learning approaches that require large amounts of training and validation data. This paper addresses the data generation bottleneck to develop and validate such methods by proposing an integrated toolchain based on deterministic channel modeling and radio propagation simulation. The toolchain is demonstrated exemplary for scenario classification to obtain localization-related channel parameters within an aircraft cabin environment

The forgotten cohort-lessons learned from prehospital trauma death: a retrospective cohort study.

BACKGROUND Trauma related deaths remain a relevant public health problem, in particular in the younger male population. A significant number of these deaths occur prehospitally without transfer to a hospital. These patients, sometimes termed "the forgotten cohort", are usually not included in clinical registries, resulting in a lack of information about prehospitally trauma deaths. The aim of the present study was to compare patients who died prehospital with those who sustained life-threatening injuries in order to analyze and potentially improve prehospital strategies. METHODS This cohort study included all primary operations carried out by Switzerland's largest helicopter emergency medical service (HEMS) between January 1, 2011, and December 31, 2021. We included all adult trauma patients with life-threatening or fatal conditions. The outcome of this study is the vital status of the patient at the end of mission, i.e. fatal or life-threatening. Injury, rescue characteristics, and interventions of the forgotten trauma cohort, defined as patients with a fatal injury (NACA score of VII), were compared with life-threatening injuries (NACA score V and VI). RESULTS Of 110,331 HEMS missions, 5534 primary operations were finally analyzed, including 5191 (93.8%) life-threatening and 343 (6.2%) fatal injuries. More than two-thirds of patients (n = 3772, 68.2%) had a traumatic brain injury without a significant difference between the two groups (p > 0.05). Thoracic trauma (44.6% vs. 28.7%, p < 0.001) and abdominal trauma (22.2% vs. 16.1%, p = 0.004) were more frequent in fatal missions whereas pelvic trauma was similar between the two groups (13.4% vs. 12.9%, p = 0.788). Pneumothorax decompression rate (17.2% vs. 3.7%, p < 0.001) was higher in the forgotten cohort group and measures for bleeding control (15.2% vs. 42.7%, p < 0.001) and pelvic belt application (2.9% vs. 13.1% p < 0.001) were more common in the life-threating injury group. CONCLUSION Chest decompression rates and measures for early hemorrhage control are areas for potential improvement in prehospital care

SAFER: Development and Evaluation of an IoT Device Risk Assessment Framework in a Multinational Organization

Users of Internet of Things (IoT) devices are often unaware of their security risks and cannot sufficiently factor security considerations into their device selection. This puts networks, infrastructure and users at risk. We developed and evaluated SAFER, an IoT device risk assessment framework designed to improve users' ability to assess the security of connected devices. We deployed SAFER in a large multinational organization that permits use of private devices. To evaluate the framework, we conducted a mixed-method study with 20 employees. Our findings suggest that SAFER increases users' awareness of security issues. It provides valuable advice and impacts device selection. Based on our findings, we discuss implications for the design of device risk assessment tools, with particular regard to the relationship between risk communication and user perceptions of device complexity

Quantifying systematic uncertainties in supernova cosmology

Observations of Type Ia supernovae used to map the expansion history of the Universe suffer from systematic uncertainties that need to be propagated into the estimates of cosmological parameters. We propose an iterative Monte-Carlo simulation and cosmology fitting technique (SMOCK) to investigate the impact of sources of error upon fits of the dark energy equation of state. This approach is especially useful to track the impact of non-Gaussian, correlated effects, e.g. reddening correction errors, brightness evolution of the supernovae, K-corrections, gravitational lensing, etc. While the tool is primarily aimed for studies and optimization of future instruments, we use the ``Gold'' data-set in Riess et al. (2007) to show examples of potential systematic uncertainties that could exceed the quoted statistical uncertainties.Comment: Accepted for publication in JCA

Dispersion-Theoretical Analysis of the Nucleon Electromagnetic Formfactors

Dispersion relations allow for a coherent description of the nucleon electromagnetic form factors measured over a large range of momentum transfer, $Q^2 \simeq 0 \ldots 35$ GeV$^2$. Including constraints from unitarity and perturbative QCD, we present a novel parametrisation of the absorptive parts of the various isoscalar and isovector nucleon form factors. Using the current world data, we obtain results for the electromagnetic form factors, nucleon radii and meson couplings. We stress the importance of measurements at large momentum transfer to test the predictions of perturbative QCD.Comment: 33 pp, RevTEX or plain LaTeX, 7 figures (in ffig.uu

Exclusive channels in γγ\gamma\gamma reactions: light at the end of the tunnel?

The physics that can be learnt by studying exclusive channels in two photon interactions is recalled. This serves as an introduction to the Exclusive Reaction session of Photon'99.Comment: 9 pages,8 figures. Invited introductory talk at Photon'99, Freiburg im Br., Germany, May 199

Diffusion-weighted magnetic resonance imaging using a preclinical 1 T PET/MRI in healthy and tumor-bearing rats

Background: Hybrid positron emission tomography and magnetic resonance imaging (PET/MRI) scanners are increasingly used for both clinical and preclinical imaging. Especially functional MRI sequences such as diffusionweighted imaging (DWI) are of great interest as they provide information on a molecular level, thus, can be used as surrogate biomarkers. Due to technical restrictions, MR sequences need to be adapted for each system to perform reliable imaging. There is, to our knowledge, no suitable DWI protocol for 1 Tesla PET/MRI scanners. We aimed to establish such DWI protocol with focus on the choice of b values, suitable for longitudinal monitoring of tumor characteristics in a rat liver tumor model. Material and methods: DWI was first performed in 18 healthy rat livers using the scanner-dependent maximum of 4 b values (0, 100, 200, 300 s/mm2). Apparent diffusion coefficients (ADC) were calculated from different b value combinations and compared to the reference measurement with four b values. T2-weighted MRI and optimized DWI with best agreement between accuracy, scanning time, and system performance stability were used to monitor orthotopic hepatocellular carcinomas (HCC) in five rats of which three underwent additional 2-deoxy-2-(18F)fluoro-D-glucose(FDG)-PET imaging. ADCs were calculated for the tumor and the surrounding liver parenchyma and verified by histopathological analysis. Results: Compared to the reference measurements, the combination b = 0, 200, 300 s/mm2 showed the highest correlation coefficient (rs = 0.92) and agreement while reducing the acquisition time. However, measurements with less than four b values yielded significantly higher ADCs (p < 0.001). When monitoring the HCC, an expected drop of the ADC was observed over time. These findings were paralleled by FDG-PET showing both an increase in tumor size and uptake heterogeneity. Interestingly, surrounding liver parenchyma also showed a change in ADC values revealing varying levels of inflammation by immunohistochemistry. Conclusion: We established a respiratory-gated DWI protocol for a preclinical 1 T PET/MRI scanner allowing to monitor growth-related changes in ADC values of orthotopic HCC liver tumors. By monitoring the changes in tumor ADCs over time, different cellular stages were described. However, each study needs to adapt the protocol further according to their question to generate best possible results

Human Borna disease virus 1 (BoDV-1) encephalitis cases in the north and east of Germany

In 2021, three encephalitis cases due to the Borna disease virus 1 (BoDV-1) were diagnosed in the north and east of Germany. The patients were from the states of Thuringia, Saxony-Anhalt, and Lower Saxony. All were residents of known endemic areas for animal Borna disease but without prior diagnosed human cases. Except for one recently detected case in the state of Brandenburg, all >30 notified cases had occurred in, or were linked to, the southern state of Bavaria. Of the three detected cases described here, two infections were acute, while one infection was diagnosed retrospectively from archived brain autopsy tissue samples. One of the acute cases survived, but is permanently disabled. The cases were diagnosed by various techniques (serology, molecular assays, and immunohistology) following a validated testing scheme and adhering to a proposed case definition. Two cases were classified as confirmed BoDV-1 encephalitis, while one case was a probable infection with positive serology and typical brain magnetic resonance imaging, but without molecular confirmation. Of the three cases, one full virus genome sequence could be recovered. Our report highlights the need for awareness of a BoDV-1 etiology in cryptic encephalitis cases in all areas with known animal Borna disease endemicity in Europe, including virus-endemic regions in Austria, Liechtenstein, and Switzerland. BoDV-1 should be actively tested for in acute encephalitis cases with residence or rural exposure history in known Borna disease-endemic areas.Peer Reviewe