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Objectives Low bone mineral density (BMD) was recently identified as a novel risk factor for patients with hepatocellular carcinoma (HCC). In this multicenter study, we aimed to validate the role of BMD as a prognostic factor for patients with HCC undergoing transarterial chemoembolization (TACE). Methods This retrospective multicenter trial included 908 treatment-naïve patients with HCC who were undergoing TACE as a first-line treatment, at six tertiary care centers, between 2010 and 2020. BMD was assessed by measuring the mean Hounsfield units (HUs) in the midvertebral core of the 11th thoracic vertebra, on contrast-enhanced computer tomography performed before treatment. We assessed the influence of BMD on median overall survival (OS) and performed multivariate analysis including established estimates for survival. Results The median BMD was 145 HU (IQR, 115–175 HU). Patients with a high BMD (≥ 114 HU) had a median OS of 22.2 months, while patients with a low BMD (< 114 HU) had a lower median OS of only 16.2 months (p < .001). Besides albumin, bilirubin, tumor number, and tumor diameter, BMD remained an independent prognostic factor in multivariate analysis. Conclusions BMD is an independent predictive factor for survival in elderly patients with HCC undergoing TACE. The integration of BMD into novel scoring systems could potentially improve survival prediction and clinical decision-making. Key Points • Bone mineral density can be easily assessed in routinely acquired pre-interventional computed tomography scans. • Bone mineral density is an independent predictive factor for survival in elderly patients with HCC undergoing TACE. • Thus, bone mineral density is a novel imaging biomarker for prognosis prediction in elderly patients with HCC undergoing TACE.

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.

Purpose Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. Methods In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. Results In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. Conclusions [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease.

Many pathologies of the mediastinum can be diagnosed using standard radiographs. Correlation of radiographic findings with computed tomography (CT) is instructive for a better understanding and can help improve detection rates of mediastinal lesions.To identify the most common mediastinal lesions and to correlate their features in chest radiographs and CT.The International Thymic Malignancy Interest Group (ITMIG) classification in the anterior, middle, and posterior mediastinum is based on anatomic landmarks. Used as a tool to characterize mediastinal lesions this classification is applied in this article.The most common lesions include mediastinal goiter, germ cell and thymic neoplasms in the anterior mediastinum, lymphadenopathy in the middle mediastinum, and neurogenic neoplasms in the posterior mediastinum. Other lesions of neoplastic or non-neoplastic origin can be distinguished in the three compartments and should be considered in the differential diagnosis.Knowledge of the most common pathologies in the three mediastinal compartments can accelerate differential diagnosis. Understanding the normal mediastinal lines is key in anatomic localization and detection of many lesions in chest radiographs.HINTERGRUND: Zahlreiche Pathologien des Mediastinums sind einer Diagnostik durch konventionelle Röntgenaufnahmen zugänglich. Die Korrelation der Röntgenbefunde mit der Computertomographie (CT) hilft, das Verständnis und die Detektion von mediastinalen Läsionen in der Röntgenbildgebung zu verbessern.Die häufigsten mediastinalen Läsionen sollen identifiziert und ihr Erscheinungsbild in der Röntgen-Thorax-Aufnahme und der CT miteinander korreliert werden.Die anatomische Gliederung in vorderes, mittleres und hinteres Mediastinum nach der International Thymic Malignancy Interest Group (ITMIG) ist ein Hilfsmittel bei der Charakterisierung mediastinaler Läsionen und wird daher auch hier angewendet.Zu den häufigsten mediastinalen Läsionen zählt die mediastinale Struma, Keimzelltumoren und Thymusneoplasien im vorderen Mediastinum, die Lymphadenopathie im mittleren Mediastinum sowie neurogene Neoplasien im hinteren Mediastinum. Weitere neoplastische und nichtneoplastische Läsionen können den 3 Kompartimenten zugeordnet werden und sollten differenzialdiagnostisch beachtet werden.Die Kenntnis der häufigsten Pathologien in den 3 mediastinalen Kompartimenten kann die Differenzialdiagnose beschleunigen. Das Verständnis der normalen Randkonturen des Mediastinums ist ein Schlüssel bei der anatomischen Verortung und Detektion vieler Läsionen in der Röntgenaufnahme des Thorax.

The concept of total neoadjuvant therapy (TNT) means a paradigm shift in the treatment of patients with rectal cancer. In cases in which the TNT induced a complete clinical response (cCR), an organ preserving watch and wait therapy concept can now be provided more often; however, this increases the demand for imaging for the determination of cCR and in the subsequent follow-up. In this article, the performance of radiology in these scenarios will be evaluated and discussed. Magnetic resonance imaging (MRI) is the current standard for local assessment of the rectum with a high sensitivity for diagnosis and staging of rectal cancer, residual tumor and tumor recurrence. However, the certain exclusion of residual malignant tissue is still difficult, in particular the differentiation of residual scar tissue from vital residual tumor is only possible with low specificity and a moderate negative predictive value (NPV). The currently discussed criteria for the assessment of imaging have not yet been validated in large cohorts and are frequently subjective. An improvement of the diagnostic accuracy for identification of cCR in patients after TNT and for monitoring patients in watch and wait treatment concepts can certainly be achieved by the integration of MRI, endoscopy and endosonography as well as clinical parameters. This should enable for identification of patients with an incomplete response or local recurrence, in time for extended treatment to be initiated without relevant impact on the patient outcome.Das Konzept der totalen neoadjuvanten Therapie (TNT) bedeutet einen Paradigmenwechsel in der Behandlung von Patienten mit Rektumkarzinom. In Fällen, in denen die TNT eine komplette klinische Remission („complete clinical response“, cCR) induziert, können nun vermehrt organerhaltende Watch-and-wait-Therapiekonzepte angeboten werden. Damit steigt allerdings der Anspruch an die begleitende Bildgebung zum einen in der Festlegung einer cCR, zum anderen im konsekutiven Follow-up. Wie sicher in diesen Szenarien die Radiologie die an sie gestellten Fragen beantworten kann, wollen wir in diesem Artikel darlegen. Die Magnetresonanztomographie (MRT) ist etablierter Standard für die lokale Beurteilung des Rektums mit hoher Sensitivität in der Diagnostik von Rektumkarzinomen, Residualtumoren sowie Rezidiven. Der sichere Ausschluss residuellen malignen Gewebes gestaltet sich jedoch schwierig, insbesondere ist die Differenzierung narbiger, avitaler Residuen von relevantem Resttumor mit nur niedriger Spezifität und mäßigem negativ prädiktivem Wert (NPV) möglich. Bisher für die Bildbeurteilung diskutierte Kriterien sind noch nicht breit objektiviert oder in großen Kohorten validiert worden. Eine Verbesserung der diagnostischen Genauigkeit zur Identifikation von Patienten mit cCR nach TNT und dem Monitoring im Rahmen von Watch-and-wait-Therapiekonzepten kann sicherlich durch eine integrierte Beurteilung von MRT-Bildgebung, Endoskopie und Endosonographie sowie klinischen Parametern erreicht werden. Fälle einer inkompletten Response oder eines Lokalrezidivs wird man auf diese Weise rechtzeitig sicher detektieren und eine weitergehende Therapie einleiten können, ohne dass sich dies relevant im Outcome der Patienten niederschlägt.

Iron oxide nanoparticles (ION) are highly sensitive probes for magnetic resonance imaging (MRI) that have previously been used for in vivo cell tracking and have enabled implementation of several diagnostic tools to detect and monitor disease. However, the in vivo MRI signal of ION can overlap with the signal from endogenous iron, resulting in a lack of detection specificity. Therefore, the long-term fate of administered ION remains largely unknown, and possible tissue deposition of iron cannot be assessed with established methods. Herein, we combine nonradioactive 57Fe-ION MRI with ex vivo laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging, enabling unambiguous differentiation between endogenous iron (56Fe) and iron originating from applied ION in mice. We establish 57Fe-ION as an in vivo MRI sensor for cell tracking in a mouse model of subcutaneous inflammation and for assessing the long-term fate of 57Fe-ION. Our approach resolves the lack of detection specificity in ION imaging by unambiguously recording a 57Fe signature.

Cancer immunotherapies play an increasing role in the treatment of advanced cancer. In a subset of patients, atypical response patterns and unconventional adverse events make diagnostic evaluation challenging for radiologists.In this article, we provide a review of the possibilities and limitations of imaging methods in monitoring immunotherapies, discuss the phenomena of pseudoprogression and hyperprogression, and introduce iRECIST as an evaluation standard for clinical studies with immunotherapies. In addition, we describe the most notable adverse events and their imaging features.This article is based on reviews and studies published since 2009. We used PubMed for the literature search and included the following search terms: "immunotherapy", "checkpoint inhibitor", "pseudoprogression", "iRECIST" and "immune related adverse events".With an incidence of up to 10%, pseudoprogression is a rare phenomenon. Currently, differentiation between pseudoprogression and true progressive disease is only possible by follow-up examinations. iRECIST, published in 2017, introduced immune unconfirmed progressive disease (iUPD) and immune confirmed progressive disease (iCPD) as new categories of therapeutic response. There is still no consensus on the time interval between examinations. Crucial adverse events include hypophysitis and pneumonitis, whereby the latter may present as different patterns of interstitial pneumonia making it difficult to differentiate between drug toxicity, infection, and tumor progression.

Tissue has characteristic properties when it comes to light absorption and scattering. For optical (OI) and optoacoustic imaging (OAI) these properties can be utilised to visualise biological tissue characteristics, as, for example, the oxygenation state of haemoglobin alters the optical and optoacoustic properties of the molecule.

This study aimed at evaluating hybrid multispectral optoacoustic tomography/ultrasound for imaging of thyroid disorders, including Graves' disease and thyroid nodules. Methods: The functional biomarkers and tissue parameters deoxygenated hemoglobin, oxygenated hemoglobin, total hemoglobin, saturation of hemoglobin, fat content, and water content were analyzed in thyroid lobes affected by Graves' disease (n = 6), thyroid lobes with healthy tissue (n = 8), benign thyroid nodules (n = 13), and malignant thyroid nodules (n = 3). Results: In Graves' disease, significantly higher deoxygenated hemoglobin (3.18 ± 0.52 vs. 2.13 ± 0.62; P = 0.0055) and total hemoglobin (8.34 ± 0.88 vs. 6.59 ± 1.16; P = 0.0084) and significantly lower fat content (0.64 ± 0.37 vs. 1.69 ± 1.25; P = 0.0293) were found than in healthy controls. Malignant thyroid nodules showed significantly lower saturation of hemoglobin (55.4% ± 2.6% vs. 60.8% ± 7.2%; P = 0.0393) and lower fat content (0.62 ± 0.19 vs. 1.46 ± 0.87; P = 0.1295) than benign nodules. Conclusion: This pilot study showed the applicability and the potential of hybrid multispectral optoacoustic tomography/ultrasound to semiquantitatively provide tissue characterization and functional parameters in thyroid disorders for improved noninvasive diagnostics of thyroid diseases.

Iron oxide nanoparticles (ION) are highly sensitive probes for magnetic resonance imaging (MRI) that have previously been used for in vivo cell tracking and have enabled implementation of several diagnostic tools to detect and monitor disease. However, the in vivo MRI signal of ION can overlap with the signal from endogenous iron, resulting in a lack of detection specificity. Therefore, the long-term fate of administered ION remains largely unknown, and possible tissue deposition of iron cannot be assessed with established methods. Herein, we combine nonradioactive

Purpose Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. Methods In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. Results In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. Conclusions [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease. Electronic supplementary material The online version of this article (10.1007/s00259-019-04662-4) contains supplementary material, which is available to authorized users.

Owing to improvements in our understanding of the biological principles of tumour initiation and progression, a wide variety of novel targeted therapies have been developed. Developments in biomedical imaging, however, have not kept pace with these improvements and are still mainly designed to determine lesion size alone, which is reflected in the Response Evaluation Criteria in Solid Tumors (RECIST). Imaging approaches currently used for the evaluation of treatment responses in patients with solid tumours, therefore, often fail to detect successful responses to novel targeted agents and might even falsely suggest disease progression, a scenario known as pseudoprogression. The ability to differentiate between responders and nonresponders early in the course of treatment is essential to allowing the early adjustment of treatment regimens. Various imaging approaches targeting a single dedicated tumour feature, as described in the hallmarks of cancer, have been successful in preclinical investigations, and some have been evaluated in pilot clinical trials. However, these approaches have largely not been implemented in clinical practice. In this Review, we describe current biomedical imaging approaches used to monitor responses to treatment in patients receiving novel targeted therapies, including a summary of the most promising future approaches and how these might improve clinical practice. The development of more-targeted cancer therapies has not been matched by more-targeted imaging methods. This discrepancy has, in some scenarios, resulted in inaccurate assessments of the effects of novel therapies. In this Review, the authors describe potential novel imaging approaches that could be adopted to enable improvements in imaging-based monitoring of treatment responses and resistance.

Tumor-associated macrophages (TAMs) represent the largest group of leukocytes within the tumor microenvironment (TME) of solid tumors and orchestrate the composition of anti- as well as pro-tumorigenic factors. This makes TAMs an excellent target for novel cancer therapies. The plasticity of TAMs resulting in varying membrane receptors and expression of intracellular proteins allow the specific characterization of different subsets of TAMs. Those markers similarly allow tracking of TAMs by different means of molecular imaging. This review aims to provides an overview of the origin of tumor-associated macrophages, their polarization in different subtypes, and how characteristic markers of the subtypes can be used as targets for molecular imaging and theranostic approaches.

Background and PurposeNew therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A-I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis. Experimental ApproachDaily injections of 5A peptide, a synthetic bihelical apoA-I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v(-1)) dextran sodium sulfate (DSS) in drinking water or healthy controls. Key ResultsDaily treatment with 5A peptide potently restricted DSS-induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNF and IL-6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein-1 and the monocyte expression of adhesion-mediating molecule CD11b were down-regulated, pro-inflammatory CD11b(+)/Ly6c(high) monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide-treated animals as determined by intravital macrophage-related peptide-8/14-directed fluorescence-mediated tomography and post-mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM-1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNF-stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS-induced inflammation was noted in apoA-I-/- mice. Conclusions and ImplicationsThe 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA-I mimetics as a potential treatment approach for IBD.

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.

The study aimed to evaluate the clinical feasibility of hybrid ultrasound/multispectral optoacoustic tomography (MSOT) for assessing microvascular dysfunction in systemic sclerosis (SSc). A handheld US/MSOT imaging system was applied for imaging patients diagnosed with SSc (n = 7) and healthy volunteers (n = 8). Semiquantitative MSOT values for deoxygenated (HbR), oxygenated (HbO(2)) and total haemoglobin (HbT) were analysed for subcutaneous finger tissue of both hands (8 fingers per subject, 120 fingers in total) and used to assess disease activity (progressive vs stable). Grouped data were compared by one-way nested analysis of variance, Tukey post-hoc test as well as student's t test were used for statistical analysis.Subcutaneous finger tissue of patients with SSc provided significantly lower MSOT values for HbO(2) (26.16 +/- 0.71 vs 38.2 +/- 1.54, P =.023) and HbT (55.92 +/- 1.62 vs 72.46 +/- 1.90, P =.018) compared to healthy volunteers. Patients with progressive SSc had significantly lower MSOT values compared to patients with stable disease and healthy volunteers.This pilot study shows the feasibility of MSOT imaging to resolve microvascular dysfunction in SSc as a marker of disease activity. By providing biological tissue properties not revealed by other imaging modalities, MSOT might help to grade SSc non-invasively and monitor early therapy response.

Murine models of disease are indispensable to scientific research. However, many diagnostic tools such as endoscopy or tomographic imaging are not routinely employed in animal models. Conventional experimental readouts often rely on post mortem and ex vivo analyses, which prevent intra-individual follow-up examinations and increase the number of study animals needed. Fluorescence-mediated tomography enables the non-invasive, repetitive, quantitative, three-dimensional assessment of fluorescent probes. It is highly sensitive and permits the use of molecular makers, which allows for the specific detection and characterization of distinct molecular targets. In particular, targeted probes represent an innovative tool for analyzing gene activation and protein expression in inflammation, autoimmune disease, infection, vascular disease, cell migration, tumorigenesis, etc. In this article, we provide step-by-step instructions on this sophisticated imaging technology for the in vivo detection and characterization of inflammation (i.e., F4/80-positive macrophage infiltration) in a widely used murine model of intestinal inflammation. This technique might also be used in other research areas, such as immune cell or stem cell tracking.

Multispectral optoacoustic tomography (MSOT) represents a new in vivo imaging technique with high resolution (~250 μm) and tissue penetration (>1 cm) using the photoacoustic effect. While ultrasound contains anatomical information for lesion detection, MSOT provides functional information based on intrinsic tissue chromophores. We aimed to evaluate the feasibility of combined ultrasound/MSOT imaging of breast cancer in patients compared to healthy volunteers. Imaging was performed using a handheld MSOT system for clinical use in healthy volunteers (n = 6) and representative patients with histologically confirmed invasive breast carcinoma (n = 5) and ductal carcinoma in situ (DCIS, n = 2). MSOT values for haemoglobin and oxygen saturation were assessed at 0.5, 1.0 and 1.5 cm depth and selected wavelengths between 700 and 850 nm. Reproducible signals were obtained in all wavelengths with consistent MSOT signals in superficial tissue in breasts of healthy individuals. In contrast, we found increased signals for haemoglobin in invasive carcinoma, suggesting a higher perfusion of the tumour and tumour environment. For DCIS, MSOT values showed only little variation compared to healthy tissue. This preliminary MSOT breast imaging study provided stable, reproducible data on tissue composition and physiological properties, potentially enabling differentiation of solid malignant and healthy tissue. • A handheld MSOT probe enables real-time molecular imaging of the breast. • MSOT of healthy controls provides a reproducible reference for pathology identification. • MSOT parameters allows for differentiation of invasive carcinoma and healthy tissue.

Integrins are heterodimeric transmembrane protein receptors consisting of different α and β subunits. α(v)β(3) integrins are overexpressed on many tumor cells and tumor-associated angiogenic vessels, whereas α(IIb)β(3) is a receptor for, e.g., fibrinogen and mediates platelet aggregation. In this study, a near-infrared fluorescent imaging probe has been designed and synthesized by conjugating fluorescent dyes to a non-peptidic, pharmacophore-based ligand, based on a molecular modeling design approach. Affinity values were determined, and in vitro cell binding assays and preliminary in vivo xenograft studies in nude mice were performed to evaluate target binding. Competition assays revealed excellent binding and selectivity to α(v)β(3) compared to that for α(IIb)β(3). In vitro, the probe showed high target binding on α(v)β(3)-positive M-21 cells and negligible binding to α(v)β(3)-negative MCF-7 cells. In vivo, the tracer is able to image target expression in U-87 xenografts with a maximum signal-to-noise ratio (SNR) of 2.5:1 at 24 h after injection.

Tumor necrosis factor α (TNFα) is the prototype of a proinflammatory cytokine that is mainly secreted by activated macrophages, but also by keratinocytes, fibroblasts, and endothelial cells. It plays a key role in activation of immune cells during the acute phase of inflammation, but it also regulates fundamental cell responses such as proliferation, differentiation, and apoptosis (1). When dysregulated, TNFα displays several pathologic activities resulting in the development of acute and chronic pathologies, among which psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are the most prominent (2–4). In addition to attraction and activation of immune cells, TNFα also activates synovial fibroblasts, keratinocytes, and osteoclasts, which in turn, secrete further cytokines, chemokines, and alarmins, thus potentiating a proinflammatory state and tissue damage. Furthermore, the alarmins S100A8 and S100A9 have been shown to act in a concerted manner with TNFα. S100A8 and S100A9 up-regulate TNFα expression and TNFα up-regulates S100A8 and S100A9 expression in a functional feedback loop, and both S100A8 and S100A9 are involved in induction of matrix metalloproteinases (MMPs) (5,6), contributing significantly to inflammation, cartilage damage, and bone resorption (7–9). Considering the great importance of TNFα for the induction and progression of arthritis, it is not surprising that several mouse models overexpressing the TNFα cytokine have been established. The first was generated by Keffer et al in 1991 (10). This transgenic mouse contains the complete genomic sequence of the human TNFα gene. Only the 3′-noncoding region was replaced by the 3′-untranslated region (3′-UTR) of the human β-globin gene. These mice constitutively express the human TNFα cytokine and, 10 weeks after birth, develop a severe form of RA that affects primarily ankle joints. Other transgenic models soon followed. They constitutively express either a human or a mouse TNFα transgene with a deleted or modified 3′-UTR. These transgenic mice, as well as the tristetraprolin-knockout mouse, all developed arthritic diseases of differing severity and allowed the deciphering of many molecular details underlying their development (4,11). However, TNFα-transgenic mice usually also have impaired fertility (12). This dysfunction presents a serious hindrance in crossing them with other animals to gain more insight into the molecular mechanisms of arthritic diseases or other disorders. To overcome this problem, we generated a doxycycline-inducible human TNFα–transgenic mouse (also called an ihTNFtg mouse) in which the expression of the human TNFα gene is under the control of a tetracycline (Tet)–responsive promoter.

Integrins play an important role in tumor progression, invasion and metastasis. Therefore we aimed to evaluate a preclinical imaging approach applying ανβ3 integrin targeted hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) for monitoring tumor progression as well as early therapy response in a syngeneic murine Non-Small Cell Lung Cancer (NSCLC) model. Lewis Lung Carcinomas were grown orthotopically in C57BL/6 J mice and imaged in-vivo using a ανβ3 targeted near-infrared fluorescence (NIRF) probe. ανβ3-targeted FMT-XCT was able to track tumor progression. Cilengitide was able to substantially block the binding of the NIRF probe and suppress the imaging signal. Additionally mice were treated with an established chemotherapy regimen of Cisplatin and Bevacizumab or with a novel MEK inhibitor (Refametinib) for 2 weeks. While μCT revealed only a moderate slowdown of tumor growth, ανβ3 dependent signal decreased significantly compared to non-treated mice already at one week post treatment. ανβ3 targeted imaging might therefore become a promising tool for assessment of early therapy response in the future.

IMPORTANCE: Differential diagnosis of congenital vascular anomalies is challenging, and misdiagnosis is frequent. Vascular malformations are considered one of the most difficult vascular diseases to treat. A new imaging approach that visualizes anatomical features and quantitatively assesses molecular biomarkers noninvasively would aid diagnosis and monitoring of treatment response of vascular malformations. OBJECTIVE: To evaluate multispectral optoacoustic tomography (MSOT) for noninvasive assessment of molecular biomarkers for diagnosis and therapeutic monitoring of vascular malformations. DESIGN, SETTING, AND PARTICIPANTS: This pilot study examined 6 patients with arteriovenous malformation (AVM) and 6 patients with venous malformation (VM) diagnosed according to the classification system of the International Society for the Study of Vascular Anomalies. All patients underwent clinical hybrid MSOT/ultrasonographic (US) imaging before and after treatment at an interdisciplinary vascular malformations clinic by trained MSOT and US examiners. Examiners were blinded to the patient history and stage of disease. Data were collected from April 11 to 25, 2017, and analyzed from May 1 to October 31, 2017. INTERVENTIONS: Clinical hybrid MSOT/US imaging was performed before or within 1 week after endovascular embolization (for AVM) or percutaneous sclerotherapy (for VM). MAIN OUTCOMES AND MEASURES: Region-of-interest analysis of the lesion and contralateral healthy tissue revealed quantitative values for oxygenated (HbO(2)) and deoxygenated (HbR) hemoglobin by spectral unmixing of optoacoustic data acquired at multiple wavelengths. The HbO(2):HbR ratio was calculated for healthy tissue and for AVM and VM before and after treatment. RESULTS: Twelve patients (9 female and 3 male; mean [SD] age, 23 [18] years; age range, 6-59 years) with vascular malformations (6 with AVMs and 6 with VMs) were included. Significantly higher HbO(2):HbR ratios for AVMs (mean [SEM], 1.82 [0.08] vs 0.89 [0.03]; P

The process of angiogenesis, an essential hallmark for tumour development as well as for several inflammatory diseases and physiological phenomena, is of growing interest for diagnosis and therapy in oncology. In the context of biochemical characterisation of key molecules involved in angiogenesis, several targets for imaging and therapy could be identified in the last decade. Optical imaging (OI) relies on the visualisation of near infrared (NIR) light, either its absorption and scattering in tissue (non-enhanced OI) or using fluorescent contrast agents. OI offers excellent signal to noise ratios due to virtually absent background fluorescence in the NIR range and is thus a versatile tool to image specific molecular target structures in vivo. This work intends to provide a survey of the different approaches to imaging of angiogenesis using OI methods in preclinical research as well as first clinical trials. Different imaging modalities as well as various optical contrast agents are briefly discussed.

Objective To investigate annexin-based optical fluorescence imaging (OI) for monitoring regorafenib-induced early cell death in experimental colon carcinomas in rats, validated by perfusion MRI and multiparametric immunohistochemistry. Materials and Methods Subcutaneous human colon carcinomas (HT-29) in athymic rats (n = 16) were imaged before and after a one-week therapy with regorafenib (n = 8) or placebo (n = 8) using annexin-based OI and perfusion MRI at 3 Tesla. Optical signal-to-noise ratio (SNR) and MRI tumor perfusion parameters (plasma flow PF, mL/100mL/min;plasma volume PV,%) were assessed. On day 7, tumors underwent immunohistochemical analysis for tumor cell apoptosis (TUNEL),proliferation (Ki-67),and microvascular density (CD31). Results Apoptosis-targeted OI demonstrated a tumor-specific probe accumulation with a significant increase of tumor SNR under therapy (mean Delta +7.78 +/- 2.95, control: -0.80 +/- 2.48, p = 0.021). MRI detected a significant reduction of tumor perfusion in the therapy group (mean Delta PF -8.17 +/- 2.32 mL/100 mL/min, control -0.11 +/- 3.36 mL/100 mL/min, p = 0.036). Immunohistochemistry showed significantly more apoptosis (TUNEL;11392 +/- 1486 vs. 2921 +/- 334, p = 0.001),significantly less proliferation (Ki-67;1754 +/- 184 vs. 2883 +/- 323, p = 0.012),and significantly lower microvascular density (CD31;107 +/- 10 vs. 182 +/- 22, p = 0.006) in the therapy group. Conclusions Annexin-based OI allowed for the non-invasive monitoring of regorafenib-induced early cell death in experimental colon carcinomas, validated by perfusion MRI and multiparametric immunohistochemistry.

Inflammation has a key role in the pathogenesis of various human diseases. The early detection, localization and monitoring of inflammation are crucial for tailoring individual therapies. However, reliable biomarkers to detect local inflammatory activities and to predict disease outcome are still missing. Alarmins, which are locally released during cellular stress, are early amplifiers of inflammation. Here, using optical molecular imaging, we demonstrate that the alarmin S100A8/S100A9 serves as a sensitive local and systemic marker for the detection of even sub-clinical disease activity in inflammatory and immunological processes like irritative and allergic contact dermatitis. In a model of collagen-induced arthritis, we use S100A8/S100A9 imaging to predict the development of disease activity. Furthermore, S100A8/S100A9 can act as a very early and sensitive biomarker in experimental leishmaniasis for phagocyte activation linked to an effective Th1-response. In conclusion, the alarmin S100A8/S100A9 is a valuable and sensitive molecular target for novel imaging approaches to monitor clinically relevant inflammatory disorders on a molecular level., Alarmins are locally released during inflammation and are early amplifiers of inflammation. Here Vogl et al. show that the alarmin S100A8/S100A9 can be used as a sensitive marker to detect subclinical inflammation and follow disease progression in a variety of disease models.