Multispectral optoacoustic tomography (MSOT) represents a new imaging approach revealing functional tissue information without extrinsic contrast agents. Using a clinical combined ultrasound (US)/MSOT device, we investigated the interindividual robustness and impact of intra- and interobserver variability of MSOT values in soft tissue (muscle and subcutaneous fat) of healthy volunteers. Semiquantitative MSOT values for deoxygenated (Hb), oxygenated (HbO₂) and total hemoglobin (HbT), as well as oxygen saturation (sO₂), were calculated for both forearms in transversal and longitudinal probe orientation (n = 3, 8 measurements per subject). For intraobserver reproducibility, the same examiner investigated three subjects twice. Mean values of left vs. right forearm and transversal vs. longitudinal probe orientation were compared using an unpaired Student’s t test. Bland Altmann plots with 95% limits of agreement for absolute averages and differences were calculated. Intraclass correlation coefficients (ICC 2,k) were computed for three different examiners. We obtained reproducible and consistent MSOT values with small-to-moderate deviation for muscle and subcutaneous fat tissue. Probe orientation and body side had no impact on calculated MSOT values (p > 0.05 each). Intraobserver reproducibility revealed equable mean values with small-to-moderate deviation. For muscular tissue, good ICC was obtained for sO₂. Measurements of subcutaneous tissue revealed good-to-excellent ICCs for all calculated values. Thus, in this preliminary study on healthy individuals, clinical MSOT provided consistent and reproducible functional soft tissue characterization, independent on the investigating personnel.

Purpose: Extracellular vesicles, small vesicles carrying inter alia proteins, miRNA and RNA, are important mediators of intercellular communication. The purpose of this study was to assess the distribution of extracellular vesicles from highly malignant breast cancer and their subsequent effect on the immune cell infiltrate in target organs of metastasis. Procedures: Extracellular vesicles were isolated from the tissue culture supernatant of highly malignant 4T1 breast cancer cells or the serum of healthy BALB/c mice. The purity of the isolate was verified by electron microscopy and western blotting. Extracellular vesicles were additionally subjected to proteome analysis. After labeling with the fluorescent dye DiR, extracellular vesicles were injected into healthy BALB/c mice and their in vivo distribution was assessed using fluorescence reflectance imaging (FRI). Following ex vivo imaging of the organs, lung tissue samples were analyzed for extracellular vesicle-mediated changes of myeloid cells and T cell numbers, using flow cytometry. Proteome analysis revealed major differences in the cargo of tumor cell–derived versus extracellular vesicles from healthy serum. Results: In contrast to control extracellular vesicles, DiR-labeled extracellular vesicles from tumor cells preferentially accumulated in lung, liver, and spine. Subsequent flow cytometry of the immune cell composition of lung tissue samples revealed an increase of cytotoxic CD8+ T cells and a decrease of CD4+ T-helper cells as well as an increase in mature macrophages in response to tumor cell EV. Conclusions: In conclusion, distribution of tumor cell–derived extracellular vesicles follows a specific pattern and can be monitored, using dedicated imaging. Extracellular vesicles alter the immune cell composition in target organs of metastasis, using a specific proteome cargo.

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. Results: MTD was 3 mg/m² tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t_{1/2(terminal)} of 8 to 9 h without accumulation in daily administrations. Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.

Objectives: To evaluate work expectations of radiologists at different career levels, their fulfillment, prevalence of exhaustion, and exhaustion-associated factors. Methods: A standardized digital questionnaire was distributed internationally to radiologists of all career levels in the hospital and in ambulatory care via radiological societies and sent manually to 4500 radiologists of the largest German hospitals between December 2020 and April 2021. Statistics were based on age- and gender-adjusted regression analyses of respondents working in Germany (510 out of 594 total respondents). Results: The most frequent expectations were “joy at work” (97%) and a “good working atmosphere” (97%), which were considered fulfilled by at least 78%. The expectation of a “structured residency within the regular time interval” (79%) was more frequently judged fulfilled by senior physicians (83%, odds ratio (OR) 4.31 [95% confidence interval (95% CI) 1.95–9.52]), chief physicians (85%, 6.81 [95% CI 1.91–24.29]), and radiologists outside the hospital (88%, 7.59 [95% CI 2.40–24.03]) than by residents (68%). Exhaustion was most common among residents (physical exhaustion: 38%; emotional exhaustion: 36%), in-hospital specialists (29%; 38%), and senior physicians (30%; 29%). In contrast to paid extra hours, unpaid extra hours were associated with physical exhaustion (5–10 extra hours: OR 2.54 [95% CI 1.54–4.19]). Fewer opportunities to shape the work environment were related to a higher probability of physical (2.03 [95% CI 1.32–3.13]) and emotional (2.15 [95% CI 1.39–3.33]) exhaustion. Conclusions: While most radiologists enjoy their work, residents wish for more training structure. Ensuring payment of extra hours and employee empowerment may help preventing burnout in high-risk groups. Key Points: • Most important work expectations of radiologists who work in Germany are “joy at work,” a “good working atmosphere,” “support for further qualification,” and a “structured residency within the regular time interval,” with the latter containing potential for improvement according to residents. • Physical and emotional exhaustion are common at all career levels except for chief physicians and for radiologists who work outside the hospital in ambulatory care. • Exhaustion as a major burnout criterion is associated with unpaid extra hours and reduced opportunities to shape the work environment.

Objective: The objective of this study was to non-invasively differentiate the degree of malignancy in two murine breast cancer models based on identification of distinct tissue characteristics in a metastatic and non-metastatic tumor model using a multiparametric Magnetic Resonance Imaging (MRI) approach.Methods: The highly metastatic 4T1 breast cancer model was compared to the non-metastatic 67NR model. Imaging was conducted on a 9.4 T small animal MRI. The protocol was used to characterize tumors regarding their structural composition, including heterogeneity, intratumoral edema and hemorrhage, as well as endothelial permeability using apparent diffusion coefficient (ADC), T1/T2 mapping and dynamic contrast-enhanced (DCE) imaging. Mice were assessed on either day three, six or nine, with an i.v. injection of the albumin-binding contrast agent gadofosveset. Ex vivo validation of the results was performed with laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), histology, immunhistochemistry and electron microscopy.Results: Significant differences in tumor composition were observed over time and between 4T1 and 67NR tumors. 4T1 tumors showed distorted blood vessels with a thin endothelial layer, resulting in a slower increase in signal intensity after injection of the contrast agent. Higher permeability was further reflected in higher K_trans values, with consecutive retention of gadolinium in the tumor interstitium visible in MRI. 67NR tumors exhibited blood vessels with a thicker and more intact endothelial layer, resulting in higher peak enhancement, as well as higher maximum slope and area under the curve, but also a visible wash-out of the contrast agent and thus lower K_trans values. A decreasing accumulation of gadolinium during tumor progression was also visible in both models in LA-ICP-MS. Tissue composition of 4T1 tumors was more heterogeneous, with intratumoral hemorrhage and necrosis and corresponding higher T1 and T2 relaxation times, while 67NR tumors mainly consisted of densely packed tumor cells. Histogram analysis of ADC showed higher values of mean ADC, histogram kurtosis, range and the 90^th percentile (p90), as markers for the heterogenous structural composition of 4T1 tumors. Principal component analysis (PCA) discriminated well between the two tumor models.Conclusions: Multiparametric MRI as presented in this study enables for the estimation of malignant potential in the two studied tumor models via the assessment of certain tumor features over time.

Prediction of response to percutaneous sclerotherapy in patients with venous malformations (VM) is currently not possible with baseline clinical or imaging characteristics. This prospective single-center study aimed to predict treatment outcome of percutaneous sclerotherapy as measured by quality of life (QoL) by using radiomic analysis of diffusion-weighted (dw) magnetic resonance imaging (MRI) before and after first percutaneous sclerotherapy. In all patients (n = 16) pre-interventional (PRE-) and delta (DELTA-) radiomic features (RF) were extracted from dw-MRI before and after first percutaneous sclerotherapy with ethanol gel or polidocanol foam, while QoL was assessed using the Toronto Extremity Salvage Score (TESS) and the 36-Item Short Form Survey (SF-36) health questionnaire. For selecting features that allow differentiation of clinical response, a stepwise dimension reduction was performed. Logistic regression models were fitted and selected PRE-/DELTA-RF were tested for their predictive value. QoL improved significantly after percutaneous sclerotherapy. While no common baseline patient characteristics were able to predict response to percutaneous sclerotherapy, the radiomics signature of VMs (independent PRE/DELTA-RF) revealed high potential for the prediction of clinical response after percutaneous sclerotherapy. This proof-of-concept study provides first evidence on the potential predictive value of (delta) radiomic analysis from diffusion-weighted MRI for Quality-of-Life outcome after percutaneous sclerotherapy in patients with venous malformations.