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Pancreatic cancer (PC) remains the fourth leading cause of cancer death; therefore, there is a clinically unmet need for novel therapeutics and diagnostic markers to treat this devastating disease. Physicians often rely on biopsy or CT for diagnosis, but more specific protein biomarkers are highly desired to assess the stage and severity of PC in a noninvasive manner. Serum biomarkers such as carbohydrate antigen 19-9 are of particular interest as they are commonly elevated in PC but have exhibited suboptimal performance in the clinic. MUC5AC has emerged as a useful serum biomarker that is specific for PC versus inflammation. We developed RA96, an anti-MUC5AC antibody, to gauge its utility in PC diagnosis through immunohistochemical analysis and whole-body PET in PC. Methods: In this study, extensive biochemical characterization determined MUC5AC as the antigen for RA96. We then determined the utility of RA96 for MUC5AC immunohistochemistry on clinical PC and preclinical PC. Finally, we radiolabeled RA96 with (89)Zr to assess its application as a whole-body PET radiotracer for MUC5AC quantification in PC. Results: Immunohistochemical staining with RA96 distinguished chronic pancreatitis, pancreatic intraepithelial neoplasia, and varying grades of pancreatic ductal adenocarcinoma in clinical samples. (89)Zr-desferrioxamine-RA96 was able to detect MUC5AC with high specificity in mice bearing capan-2 xenografts. Conclusion: Our study demonstrated that RA96 can differentiate between inflammation and PC, improving the fidelity of PC diagnosis. Our immuno-PET tracer (89)Zr-desferrioxamine-RA96 shows specific detection of MUC5AC-positive tumors in vivo, highlighting the utility of MUC5AC targeting for diagnosis of PC.

Trametinib is an extremely potent allosteric inhibitor of mitogen-activated protein kinase (MAPK)/extracellular-signal–regulated kinase (ERK) (MEK) 1/2, which has been approved for treatment of metastatic melanoma and anaplastic thyroid cancer in patients with confirmed BRAF(V600E)/K mutations. Though trametinib is highly efficacious, adverse side effects, including skin, gastrointestinal, and hepatic toxicity, are dose-limiting and can lead to treatment termination. Development of a noninvasive tool to visualize and quantify the delivery and distribution of trametinib (either as a single agent or in combination with other therapeutics) to tumors and organs would be helpful in assessing therapeutic index, personalizing individual dose, and potentially predicting resistance to therapy. Methods: To address these issues, we have developed a radiolabeled trametinib and evaluated the in vitro and in vivo properties. (123)I-, (124)I-, and (131)I-trametinib, pure tracer analogs to trametinib, were synthesized in more than 95% purity, with an average yield of 69.7% and more than 100 GBq/μmol specific activity. Results: Overall, (124)I-trametinib uptake in a panel of cancer cell lines can be blocked with cold trametinib, confirming specificity of the radiotracer in vitro and in vivo. (124)I-trametinib was taken up at higher rates in KRAS and BRAF mutant cell lines than in wild-type KRAS cancer cell lines. In vivo, biodistribution revealed high uptake in the liver 2 h after injection, followed by clearance through the gastrointestinal tract over 4 d. Importantly, uptake higher than expected was observed in the lung and heart for up to 24 h. Peak uptake in the skin and gastrointestinal tract was observed between 6 and 24 h, whereas in B16F10 melanoma–bearing mice peak tumor concentrations were achieved between 24 and 48 h. Tumor uptake relative to muscle and skin was relatively low, peaking at 3.4- to 8.1-fold by 72 h, respectively. The biodistribution of (124)I-trametinib was significantly reduced in mice on trametinib therapy, providing a quantitative method to observe MEK inhibition in vivo. Conclusion: (124)I-trametinib serves as an in vivo tool to personalize the dose instead of using the current single-fixed-dose scheme and, when combined with radiomic data, to monitor the emergence of therapy resistance. In addition, the production of iodinated trametinib affords researchers the ability to measure drug distribution for improved drug delivery studies.

The presence of metastasis in local lymph nodes (LNs) is a key factor influencing choice of therapy and prognosis in cervical and endometrial cancers; therefore, the exploration of sentinel LNs (SLNs) is highly important. Currently, however, SLN mapping requires LN biopsy for pathologic evaluation, since there are no clinical imaging approaches that can identify tumor-positive LNs in early stages. Staging lymphadenectomy poses risks, such as leg lymphedema or lymphocyst formation. Furthermore, in 80%-90% of patients, the explored LNs are ultimately tumor-free, meaning most patients are unnecessarily subjected to lymphadenectomy. Methods: Current lymphoscintigraphy methods identify only the anatomic location of the SLNs and do not provide information on their tumor status. There are no noninvasive methods to reliably identify metastases in LNs before surgery. We have developed positron lymphography (PLG), a method to detect tumor-positive LNs, in which 18F-FDG is injected interstitially into the uterine cervix on the day of surgery, and its rapid transport through the lymphatic vessels to the SLN is then visualized with dynamic PET/CT. We previously showed that PLG was able to identify metastatic LNs in animal models. Here, we present the first results from our pilot clinical trial (clinical trials identifier NCT02285192) in 23 patients with uterine or cervical cancer. On the morning of surgery, 18F-FDG was injected into the cervix, followed by an immediate dynamic PET/CT scan of the pelvis and a delayed 1-h whole-body scan. Results: There were 3 (15%) node-positive cases on final pathologic analysis, and all of these LNs (including 1 with a focus of only 80 tumor cells) were identified by PLG. There were 2 (10%) false-positive cases with PLG, in which the final pathology of the corresponding SLNs was negative for tumor. Conclusion: This first-in-humans study of PLG in women with uterine and cervical cancer demonstrates its feasibility and its ability to identify patients with nodal metastases and warrants further evaluation in additional studies.

Acute myeloid leukaemia (AML) is a fatal disease for most patients. We have found that ferumoxytol (Feraheme®), a FDA approved iron oxide nanoparticle for iron deficiency treatment, demonstrates an anti-leukaemia effect in vitro and in vivo. Using leukaemia cell lines and primary AML patient samples, we show that low expression of the iron exporter ferroportin (FPN) results in a susceptibility of these cells by an increase in intracellular iron from ferumoxytol. The reactive oxygen species produced by free ferrous iron leads to increased oxidative stress and cell death. Ferumoxytol treatment results in a significant reduction of disease burden in a murine leukaemia model and patient-derived xenotransplants (PDX) bearing leukaemia cells with low FPN expression. Our findings show how a clinical nanoparticle considered previously largely biologically inert could be rapidly incorporated into clinical trials for patients with leukaemia with low FPN levels., One Sentence Summary: Administration of the clinically approved iron oxide nanoparticle drug ferumoxytol in vitro results in an anti-leukaemia effect and in vivo extended overall survival in part due to the low expression of the iron export protein ferroportin.

Cerenkov luminescence is a blue-weighted emission of light produced by a vast array of clinically approved radioisotopes and LINAC accelerators. When β particles (emitted during the decay of radioisotopes) are present in a medium such as water or tissue, they are able to travel faster than the speed of light in that medium and in doing so polarize the molecules around them. Once the particle has left the local area, the polarized molecules relax and return to their baseline state releasing the additional energy as light (luminescence). This blue glow has commonly been used to determine the output of nuclear power plant cores and, in recent years, has found traction in the preclinical and clinical imaging field. This brief review will discuss the technology which has enabled the emergence of the biomedical Cerenkov imaging field, recent pre-clinical studies with potential clinical translation of Cerenkov luminescence imaging and the current clinical implementations of the method. Finally, an outlook is given as to the direction in which the field is heading.

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy., Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells.

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a novel human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggered clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

Cerenkov luminescence (CL) is blue glow light produced by charged subatomic particles travelling faster than the phase velocity of light in a dielectric medium such as water or tissue. CL was first discovered in 1934, but for biomedical research it was recognized only in 2009 after advances in optical camera sensors brought the required high sensitivity. Recently, applications of CL from clinical radionuclides have been rapidly expanding to include not only preclinical and clinical biomedical imaging but also an approach to therapy. Cerenkov Luminescence Imaging (CLI) utilizes CL generated from clinically relevant radionuclides alongside optical imaging instrumentation. CLI is advantageous over traditional nuclear imaging methods in terms of infrastructure cost, resolution, and imaging time. Furthermore, CLI is a truly multimodal imaging method where the same agent can be detected by two independent modalities, with optical (CL) imaging and with positron emission tomography (PET) imaging. CL has been combined with small molecules, biomolecules and nanoparticles to improve diagnosis and therapy in cancer research. Here, we cover the fundamental breakthroughs and recent advances in reagents and instrumentation methods for CLI as well as therapeutic application of CL.

Epileptic foci in mice can be better visualized with magnetic resonance imaging by using an intravenously administered nanoparticle that crosses the blood–brain barrier and is sensitive to the abnormal electrical activity of foci.

Novel translational approaches based on clinical modular nanoplatforms are needed, in order to treat solid cancers according to their discrete molecular features. In the present study, we show that the clinical nanopharmaceutical Ferumoxytol, which consists of a glucose-based coat surrounding an iron oxide core, could identify molecular characteristics of prostate cancer, corresponding to unique phases of the disease continuum. By affixing a targeting probe for the prostate-specific membrane antigen on its surface, the nanopharmaceutical was able to assess the functional state of the androgen receptor pathway via MRI, guiding therapy and delivering it with the same clinical nanoparticle. In order to simultaneously inhibit oncogenic signaling from key oncogenic pathways of more advanced forms of prostate cancer, a single-agent therapy for early-stage disease to inhibit DNA replication, as well as combination therapy with two drugs co-retained within the nanopharmaceutical’s polymeric coating, were tested, and resulted complete tumor ablation. Recalcitrant and terminal forms of the disease were effectively treated with a nanoparmaceutical delivering a combination that upregulates endoplasmic reticulum stress and inhibits metastasis, thereby showing that this multifunctional nanoplatfom can be used in the clinic for patient stratification, as well as precision treatment based on the individual’s unique disease features.

Wolfgang A. Weber and Johannes Czernin Scientific discoveries published in The Journal of Nuclear Medicine over the past 60 years have shaped the practice of medicine and form the foundation for the future of nuclear medicine, molecular imaging, and theranostics. Nuclear medicine now provides

Cooperative Intelligent Transport Systems (C-ITS) have seen increased interest in recent years, with several ongoing activities and first practical implementations. While clearly V2X-communication will play a significant role in all C-ITS deployments, several key components, such as the wireless communication technology and the message formats, are still evolving. This calls for a modular approach when designing C-ITS infrastructure, especially when considering a real world urban environment. Such environments are characterized by heterogeneous traffic light hardware and traffic management systems.This paper focuses on the modular architecture of the C-ITS pilot in Dresden. For example, a highly flexible communication stack is developed for this special purpose. It fully supports the message types standardized by European Telecommunications Standards Institute (ETSI) on the one hand, while on the other hand allowing the rapid implementation and test of novel message types and contents. This went hand in hand with the development of a modular roadside unit, enabling the rapid implementation of service applications on its central processing unit. In combination with a cloud-based backend, a real-time C-ITS service platform with a hybrid communication concept is developed.This paper presents a modular architecture and best practice guidelines based on experiences of the C-ITS pilot in Dresden. First results of research topics, such as latency measurements, are shown.The ongoing C-ITS deployment in Dresden is part of the initiative "Synchrone Mobilitat 2023", which aims at advancing Intelligent Transport Systems. Focusing on automated and connected driving in urban areas, the research and development projects under its umbrella initiate scientific and technological developments and provide comprehensive test facilities. Automated and connected driving in urban areas requires not only simulations and test drives on test sites but also enormous testing effort under real traffic conditions. The Dresden Testbed offers outstanding conditions to conduct real-world test with a multitude of test kilometers and the experience of different traffic scenarios.

The effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we demonstrate that clinically approved iron oxide nanoparticles (Ferumoxytol) can be utilized to carry one or multiple drugs. These so called 'nanophores' retain their cargo within their polymeric coating through weak electrostatic interactions and release it in slightly acidic conditions (pH 6.8 and below). The loading of drugs increases the nanophores' transverse T2 and longitudinal T1 nuclear magnetic resonance (NMR) proton relaxation times, which is proportional to amount of carried cargo. Chemotherapy with translational nanophores is more effective than the free drug in vitro and in vivo, without subjecting the drugs or the carrier nanoparticle to any chemical modification. Evaluation of cargo incorporation and payload levels in vitro and in vivo can be assessed via benchtop magnetic relaxometers, common NMR instruments or magnetic resonance imaging scanners.

Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1G37R or SOD1G93A mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.

Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Positron lymphography using 18F-FDG followed by Cerenkov-guided resection of lymph nodes in healthy mice has previously been introduced by our group. Our aim in this study was to further assess the technique’s potential beyond merely localizing sentinel lymph nodes. We now aimed to evaluate the potential of positron lymphography to characterize the nodes with respect to their tumor status in order to identify metastatic lymph nodes. We explored whether metastatic nodes could be distinguished from normal nodes via dynamic 18F-FDG lymphography, to then be resected under Cerenkov imaging guidance. Methods: A murine melanoma cell line highly metastatic to lymph nodes (B16F10) was implanted subcutaneously on the dorsal hind paw of C57 mice while the tumor-free contralateral leg served as an intraindividual control. A model of reactive lymph nodes after concanavalin A challenge served as an additional control to provide nonmalignant inflammatory lymphadenopathy. Dynamic PET/CT imaging was performed immediately after injection of 18F-FDG around the tumor or intracutaneously in the contralateral footpad. Furthermore, PET/CT and Cerenkov studies were performed repeatedly over time to follow the course of metastatic spread. In selected mice, popliteal lymph nodes underwent Cerenkov luminescence imaging. Hematoxylin and eosin staining was done to verify the presence of lymphatic melanoma infiltration. Results: Positron lymphography using 18F-FDG was successfully performed on tumor-bearing and non–tumor-bearing mice, as well as on controls bearing sites of inflammation; the results clearly identified the sentinel lymph node basin and delineated the lymphatic drainage. Significantly prolonged retention of activity was evident in metastatic nodes as compared with controls without tumor. On the basis of these results, the contrast in detection and identification of metastatic lymph nodes was distinct and could be used for guided lymph node resection, such as by using Cerenkov luminescence imaging. However, retention after 18F-FDG lymphography was also seen in acute inflammatory lymphadenopathy. Conclusion: In a tumor model, significantly longer retention of the radiotracer during 18F-FDG lymphography was seen in metastatic than nonmetastatic lymph nodes, allowing for differentiation between the two and for selective resection of tumor-bearing nodes using Cerenkov imaging. Inflammation can be better differentiated in a subacute state.

The epidemiology of prostate cancer has dramatically changed since the introduction of prostate-specific antigen (PSA) screening in the 1980’s. Most prostate cancers today are detected at early stages of the disease and are considered ‘indolent’; however, some patients’ prostate cancers demonstrate a more aggressive behaviour which leads to rapid progression and death. Increasing understanding of the biology underlying the heterogeneity that characterises this disease has led to a continuously evolving role of imaging in the management of prostate cancer. Functional and metabolic imaging techniques are gaining importance as the impact on the therapeutic paradigm has shifted from structural tumour detection alone to distinguishing patients with indolent tumours that can be managed conservatively (e.g., by active surveillance) from patients with more aggressive tumours that may require definitive treatment with surgery or radiation. In this review, we discuss advanced imaging techniques that allow direct visualisation of molecular interactions relevant to prostate cancer and their potential for translation to the clinical setting in the near future. The potential use of imaging to follow molecular events during drug therapy as well as the use of imaging agents for therapeutic purposes will also be discussed. • Advanced imaging techniques allow direct visualisation of molecular interactions in prostate cancer. • MRI/PET, optical and Cerenkov imaging facilitate the translation of molecular biology. • Multiple compounds targeting PSMA expression are currently undergoing clinical translation. • Other targets (e.g., PSA, prostate-stem cell antigen, GRPR) are in development.

Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infection of the brain caused by the JC polyomavirus (JCPyV). PML occurs when immune control of persistent infection with JCPyV fails, the virus mutates and changes its cellular tropism, enters the brain and infects astrocytes, oligodendrocytes and, in particular cases, also neurones. Currently, there is no therapy for this often fatal disease. A number of approaches have failed, and only the restoration of protective immunity, if possible, can lead to clearance of the virus once PML has occurred. During the last two decades, investigators have attempted to understand the factors contributing to the development of PML, which immune mechanisms are involved in immune surveillance, and which in clearing JCPyV from the brain once PML has occurred. Recent data suggest that both CD4+ and CD8+ T cells of the cellular immune system, and also JCPyV-specific antibodies, are involved in protection against PML and in resolving the opportunistic infection. Based on the current immunological data, prophylactic and therapeutic vaccination strategies have been proposed, and first treatment attempts in PML patients have provided promising results that indicate therapeutic vaccination may be feasible.

Shaping an X-ray beam as a thin sheet generates Cherenkov emissions that enable molecular sensing at submillimetre resolution and deep into tissue in small animals.

In the era of personalized medicine, there is an urgent need for in vivo techniques able to sensitively detect and quantify molecular activities. Sensitive imaging of gamma rays is widely used; however, radioactive decay is a physical constant, and its signal is independent of biological interactions. Here, we introduce a framework of previously uncharacterized targeted and activatable probes that are excited by a nuclear decay-derived signal to identify and measure molecular signatures of disease. We accomplished this by using Cerenkov luminescence, the light produced by β-particle-emitting radionuclides such as clinical positron emission tomography (PET) tracers. Disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence. This approach reduces background signal compared to conventional fluorescence imaging. In addition to tumor identification from a conventional PET scan, we demonstrate the medical utility of our approach by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and represents a shift toward activatable nuclear medicine agents.

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size.

In biomedical imaging, nanoparticles combined with radionuclides that generate Cerenkov luminescence are used in diagnostic imaging, photon-induced therapies and as activatable probes. In these applications, the nanoparticle is often viewed as a carrier inert to ionizing radiation from the radionuclide. However, certain phenomena such as enhanced nanoparticle luminescence and generation of reactive oxygen species cannot be completely explained by Cerenkov luminescence interactions with nanoparticles. Herein, we report methods to examine the mechanisms of nanoparticle excitation by radionuclides, including interactions with Cerenkov luminescence, β particles and γ radiation. We demonstrate that β-scintillation contributes appreciably to excitation and reactivity in certain nanoparticle systems, and that excitation by radionuclides of nanoparticles composed of large atomic number atoms generates X-rays, enabling multiplexed imaging through single photon emission computed tomography. These findings demonstrate practical optical imaging and therapy using radionuclides with emission energies below the Cerenkov threshold, thereby expanding the list of applicable radionuclides.

Nuclear medicine uses ionizing radiation for both in vivo diagnosis and therapy. Ionizing radiation comes from a variety of sources, including x-rays, beam therapy, brachytherapy, and various injected radionuclides. Although PET and SPECT remain clinical mainstays, optical readouts of ionizing radiation offer numerous benefits and complement these standard techniques. Furthermore, for ionizing radiation sources that cannot be imaged using these standard techniques, optical imaging offers a unique imaging alternative. This article reviews optical imaging of both radionuclide- and beam-based ionizing radiation from high-energy photons and charged particles through mechanisms including radioluminescence, Cerenkov luminescence, and scintillation. Therapeutically, these visible photons have been combined with photodynamic therapeutic agents preclinically for increasing therapeutic response at depths difficult to reach with external light sources. Last, new microscopy methods that allow single-cell optical imaging of radionuclides are reviewed.

In this study, we cover the convergence of radiochemistry for imaging and therapy with advances in nanoparticle (NP) design for biomedical applications. We first explore NP properties relevant for therapy and theranostics and emphasize the need for biocompatibility. We then explore radionuclide-imaging modalities such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and Cerenkov luminescence (CL) with examples utilizing radiolabeled NP for imaging. PET and SPECT have served as diagnostic workhorses in the clinic, while preclinical NP design examples of multimodal imaging with radiotracers show promise in imaging and therapy. CL expands the types of radionuclides beyond PET and SPECT tracers to include high-energy electrons (β- ) for imaging purposes. These advances in radionanomedicine will be discussed, showing the potential for radiolabeled NPs as theranostic agents. WIREs Nanomed Nanobiotechnol 2016, 8:872-890. doi: 10.1002/wnan.1402 For further resources related to this article, please visit the WIREs website.

The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of 99mTc-sulfur colloid (99mTc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media (99mTc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of 18F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from 18F-FDG was evaluated to optically guide surgical resection of LNs. Methods: Imaging of 18F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of 18F-FDG and was compared with that of 99mTc-SC. Verification of uptake and the ability to use 18F-FDG CR to guide nodal removal were confirmed histologically. Results: Intradermal injection of 18F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. 18F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection. Conclusion: Intradermal 18F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).

Molecular imaging of disease development, progression and treatment is seen as key to further advancement in the understanding and triumph over illness. The role of enzymes is to catalyze the biochemical reactions that help regulate health, and when dysregulated in complex organisms lead to or indicate disease. The ability to image the action of these proteins for diagnostic purposes opens a window for the researcher and clinician to witness specifc molecular events in vitro and in vivo. Such probes have been developed and deployed for the optical, radionuclide and magnetic resonance modalities and offer significant benefits over conventional agents. The signal of enzymatically-activated probes is regulated by the specific activity of the desired enzyme. This allows for a higher signal to background ratio over non-specific and targeted agents. It also enables the modulation of contrast agent distribution (and even cellular accumulation) following enzymatic activity. This review summarizes the strategies and probes in development and use in this emergent field of molecular imaging, with a particular focus on the research and medical relevance of these advances.

One vexing issue in biomedical research is the failure of many therapies to translate from success in animal models to effective treatment of human disease. One significant difference between the animal models and the human disease is the age of the subject. Cancer, stroke and Alzheimer's occur mainly in humans beyond the 75% mean survival age, while most mouse models use juvenile or young adult animals. Here we compare two mouse models of amyloid deposition, the Tg2576 APP model and the more aggressive APP+PS1 model in which a mutant presenilin1 gene is overexpressed with Tg2576. Middle-aged APP+PS1 mice and aged APP mice have similar degrees of amyloid pathology with a few differences that may partially explain some of the differences between the two age cohorts. The first study evaluated production of microhemorrhage by a monoclonal anti-Aβ antibody. We found that in spite of greater amyloid clearance in middle-aged APP+PS1 mice than aged APP mice, the microhemorrhage only developed in old animals. This argues that preclinical studies of immunotherapy in young or middle-aged mice may not predict this potential liability in clinical trials. A second study evaluated the infiltration of systemically injected GFP labeled monocytes into the CNS. Here we find that infiltration is greater in aged mice than middle-aged mice, in spite of greater total Aß staining in the middle-aged animals. We conclude that preclinical studies should be conducted in aged animal models as well as young mice to better prepare for unintended consequences in the human trial.

It is commonly accepted that knowledge of the degree of luminal stenosis alone is insufficient to predict a plaque’s vulnerability. Recently, several imaging techniques, such as high-resolution black-blood magnetic resonance imaging, positron emission tomography/computed tomography, ultrasound, intravascular ultrasound and computed tomography angiography, have emerged that are able to depict the arterial lumen and the vessel wall. This article will describe the potential of these imaging techniques for the identification of vulnerable plaques and will focus on the current evidence that describe the relationship between plaque imaging characterization and treatment modality selection in the coronary and carotid arteries.

Molecular imaging is aimed at the noninvasive in vivo characterization and measurement of processes at a cellular and molecular level with clinical imaging methods. Contrast agents are constructed to target markers that are specific either for certain diseases or for functional states of specialized tissues. Efforts are currently focused mainly on processes involved in angiogenesis, inflammation, and apoptosis. Cell tracking is performed for diagnostic purposes as well as for monitoring of novel cell therapies. Visualization of these processes would provide more precise information about disease expansion as well as treatment response, and could lead to a more individualized therapy for patients. Many attempts have shown promising results in preclinical studies; however, translation into the clinic remains a challenge. This applies especially to paediatrics because of more stringent safety concerns and the low prevalence of individual diseases. The most promising modalities for clinical translation are nuclear medicine methods (positron emission tomography [PET] and single photon emission CT [SPECT]) due to their high sensitivity, which allows concentrations below biological activity. However, special dose consideration is required for any application of ionizing radiation especially in children. While very little has been published on molecular imaging in a paediatric patient population beyond fluorodeoxyglucose (FDG)-PET and metaiodobenzylguanidine (MIBG) tracers, this review will attempt to discuss approaches that we believe have promise for paediatric imaging. These will include agents that already reached clinical trials as well as preclinical developments with high potential for clinical application.

PURPOSE In vitro comparison of the 6F and 8F Amplatz thrombectomy device (ATD) for treatment of thrombotically occluded vessels in a flow-model. MATERIALS AND METHODS Thrombectomy of clots from porcine blood was performed with either a 6F or an 8F Amplatz thrombectomy device (ATD) in a flow-model simulating a superficial femoral artery circuit (n = 40; 7.5 g: 7 mm diameter; 4.5 g: 5 mm diameter). Emboli caused during thrombectomy were determined in a three-step filter array (10 microns-1000 microns). RESULTS Thrombectomy was successful in all cases. In 5 mm/7 mm lumen time for thrombectomy was measured from 47 s/56s (8F) to 86 s/107 s (p < 0.01) (6F). Remaining thrombus weighted in 5 mm/7 mm lumen 0.04 g/-0.02 g (8F) and 0.05 g/-0.02 g (6F). Overall weight emboli determined for 1000 microns, 100 microns and 10 microns size and percentage of emboli related to original thrombus weight measured 0.23 g/4.96% (8F, 5 mm), 0.2 g/4.36% (6F, 5 mm), 0.08 g/1.13% (8F, 7 mm). and 0.09 g/1.18% (6F, 7 mm). CONCLUSIONS In vitro, the 6F ATD is in "vessels" with 5 mm and 7 mm diameter as effective as the 8F version. Particle embolization in flow-circuit was similar with both devices, although the 6F ATD requires a longer time for thrombectomy in vessel with larger diameter.

Background—Monocytes play a key role in atherogenesis, but their participation has been discerned largely via ex vivo analyses of atherosclerotic lesions. We sought to establish a noninvasive technique to determine monocyte trafficking to atherosclerotic lesions in live animals.Methods and Results—Using a micro–single-photon emission computed tomography small-animal imaging system and a Food and Drug Administration–approved radiotracer ([indium 111] oxyquinoline,111In-oxine), we demonstrate here that monocyte recruitment to atherosclerotic lesions can be visualized in a noninvasive, dynamic, and 3-dimensional fashion in live animals. We show in vivo that monocytes are recruited avidly to plaques within days of adoptive transfer. Using micro–single-photon emission computed tomography imaging as a screening tool, we were able to investigate modulatory effects on monocyte recruitment in live animals. We found that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors rapidly and substantially reduce monocyte recruitment to existing atherosclerotic lesions, as imaged here in vivo.Conclusions—This novel approach to track monocytes to atherosclerotic plaques in vivo should have broad applications and create new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.

Purpose To study whether multispectral optoacoustic tomography (MSOT) can serve as a label-free imaging modality for the detection of lymph node micrometastases and in-transit metastases from melanoma on the basis of the intrinsic contrast of melanin in comparison to fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Materials and Methods The study was approved by the institutional animal care and use committee. Sequential MSOT was performed in a mouse B16F10 melanoma limb lymph node metastasis model (n = 13) to survey the development of macro-, micro- and in-transit metastases (metastases that are in transit from the primary tumor site to the local nodal basin) in vivo. The in vitro limit of detection was assessed in a B16F10 cell phantom. Signal specificity was determined on the basis of a simultaneous lymphadenitis (n = 4) and 4T1 breast cancer lymph metastasis (n = 2) model. MSOT was compared with intravenous FDG PET/CT. The diagnosis was assessed with histologic examination. Differences in the signal ratio (metastatic node to contralateral limb) between the two modalities were determined with the two-tailed paired t test. Results The mean signal ratios acquired with MSOT in micrometastases (2.5 ± 0.3, n = 6) and in-transit metastases (8.3 ± 5.8, n = 4) were higher than those obtained with FDG PET/CT (1.1 ± 0.5 [P.01] and 1.3 ± 0.6 [P.05], respectively). MSOT was able to help differentiate even small melanoma lymph node metastases from the other lymphadenopathies (P.05 for both) in vivo, whereas FDG PET/CT could not (P.1 for both). In vitro, the limit of detection was at an approximate cell density of five cells per microliter (P.01). Conclusion MSOT enabled detection of melanoma lymph node micrometastases and in-transit metastases undetectable with FDG PET/CT and helped differentiate melanoma metastasis from other lymphadenopathies. (©) RSNA, 2016 Online supplemental material is available for this article.

Adoptive transfer therapy of in vitro -expanded tumor-specific cytolytic T lymphocytes (CTLs) can mediate objective cancer regression in patients. Yet, technical limitations hamper precise monitoring of posttherapy T cell responses. Here we show in a mouse model that fused single photon emission computed tomography and x-ray computed tomography allows quantitative whole-body imaging of 111 In-oxine-labeled CTLs at tumor sites. Assessment of CTL localization is rapid, noninvasive, three-dimensional, and can be repeated for longitudinal analyses. We compared the effects of lymphodepletion before adoptive transfer on CTL recruitment and report that combined treatment increased intratumoral delivery of CTLs and improved antitumor efficacy. Because 111 In-oxine is a Food and Drug Administration-approved clinical agent, and human SPECT-CT systems are available, this approach should be clinically translatable, insofar as it may assess the efficacy of immunization procedures in individual patients and lead to development of more effective therapies.

Cell based therapies such as stem cell therapies or adoptive immunotherapies are currently being explored as a potential treatment for a variety of diseases such as Parkinson's disease, diabetes or cancer. However, quantitative and qualitative evaluation of adoptively transferred cells is indispensable for monitoring the efficiency of the treatment. Current approaches mostly analyze transferred cells from peripheral blood, which cannot assess whether transferred cells actually home to and stay in the targeted tissue. Using cell-labeling methods such as direct labeling or transfection with a marker gene in conjunction with various imaging modalities (MRI, optical or nuclear imaging), labeled cells can be followed in vivo in real-time, and their accumulation as well as function in vivo can be monitored and quantified accurately. This method is usually referred to as "cell tracking" or "cell trafficking" and is also being applied in basic biological sciences, exemplified in the evaluation of genes contributing to metastasis. This review focuses on principles of this promising methodology and explains various approaches by highlighting recent examples.

90Y has been used to label various new therapeutic radiopharmaceuticals. However, measuring the radiation dose delivered by 90Y is challenging because of the absence of suitable γ emissions and its low abundance of positron emissions. For the treatment of prostate cancer, radiolabeled gastrin-releasing peptide receptor (GRPr) antagonists have yielded promising results in mouse models. In this study, we evaluated whether Cerenkov luminescence imaging (CLI) could be used to determine radiation doses of a 90Y-labeled GRPr antagonist in nude mice. Methods: Mice bearing subcutaneous prostate cancer xenografts were injected with 0.74–18.5 MBq of the 90Y-labeled GRPr antagonist DOTA-AR and underwent in vivo and ex vivo CLI at 1–48 h after injection. After imaging, animals were sacrificed, their tumors and organs were harvested, and the activity concentration was measured by liquid scintillation counting. In a second set of experiments, Cerenkov photon counts for tumor and kidney on in vivo CLI were converted to activity concentrations using conversion factors determined from the first set of experiments. Results:90Y-DOTA-AR concentration in the 3 tumor models ranged from 0.5% to 4.8% of the injected activity per gram at 1 h after injection and decreased to 0.05%–0.15 injected activity per gram by 48 h after injection. A positive correlation was found between tumor activity concentrations and in vivo CLI signal (r2 = 0.94). A similar correlation was found for the renal activity concentration and in vivo Cerenkov luminescence (r2 = 0.98). Other organs were not distinctly visualized on the in vivo images, but ex vivo CLI was also correlated with the radioactivity concentration (r2 = 0.35–0.94). Using the time–activity curves from the second experiment, we calculated radiation doses to tumor and kidney of 0.33 ± 0.12 (range, 0.21–0.66) and 0.06 ± 0.01 (range, 0.05–0.08) Gy/MBq, respectively. Conclusion: CLI is a promising, low-cost modality to measure individual radiation doses of 90Y-labeled compounds noninvasively. The use of Cerenkov imaging is expected to facilitate the development and comparison of 90Y-labeled compounds for targeted radiotherapy.

The recent years have seen significant advances in both molecular biology, allowing the identification of genes and pathways related to disease, and imaging technologies that allow for improved spatial and temporal resolution, enhanced sensitivity, better depth penetration, improved image processing, and beneficial combinations of different imaging modalities. These advances have led to a paradigm shift in the scope of diagnostic imaging. The traditional role of radiological diagnostic imaging is to define gross anatomy and structure in order to detect pathological abnormalities. Available contrast agents are mostly nonspecific and can be used to image physiological processes such as changes in blood volume, flow, and perfusion but not to demonstrate pathological alterations at molecular levels. However, alterations at the anatomical-morphological level are relatively late manifestations of underlying molecular changes. Using molecular probes or markers that bind specifically to molecular targets allows for the non-invasive visualization and quantitation of biological processes such as gene expression, apoptosis, or angio-genesis at the molecular level within intact living organisms. This rapidly evolving, multidisciplinary approach, referred to as molecular imaging, promises to enable early diagnosis, can provide improved classification of stage and severity of disease, an objective assessment of treatment efficacy, and a reliable prognosis. Furthermore, molecular imaging is an important tool for the evaluation of physiological and pathophysiological processes, and for the development of new therapies. This article comprises a review of current technologies of molecular imaging, describes the development of contrast agents and various imaging modalities, new applications in specific disease models, and potential future developments.

Lung cancer is a devastating disease that presents a challenge to basic research to provide new steps toward therapeutic advances. The cell-type-specific responses to oncogenic mutations that initiate and regulate lung cancer remain poorly defined. A better understanding of the relevant signaling pathways and mechanisms that control therapeutic outcome could also provide new insight. Improved conditional mouse models are now available as tools to improve the understanding of the cellular and molecular origins of adenocarcinoma. These models have already proven their utility in proof-of-principle experiments with new technologies including genomics and imaging. Integrated thinking to apply technological advances while using the appropriate mouse model is likely to facilitate discoveries that will significantly improve lung cancer detection and intervention.

Purpose: To determine the efficacy of thrombectomy for the Amplatz Thrombectomy Device (ATD) according to the age of the thrombus. Methods: Thrombectomy was performed with the 7 Fr or 8 Fr ATD. Five-day-old or 8-day-old thrombi were made from porcine blood by clotting within silicone tubes to be used in a flow model. Emboli sizes, weight, remaining thrombus and activation time were evaluated. Results: The age of the thrombus had no influence on the activation time necessary for complete thrombolysis. A significant difference was found in the overall amount of embolization only with the 7 Fr device although a similar trend was shown with the 8 Fr device. The amount of embolized thrombotic material was higher for both devices if older thrombi (i.e., 8 days old) were processed. The overall impression was that the 8 Fr device showed slightly better results (less remaining thrombus and embolization). Conclusion: A tendency toward higher amounts of embolization was observed if older thrombi were used in the model. Therefore the interventional radiologist should be aware of the potentially higher risk of peripheral embolization when performing mechanical thrombectomy (with the ATD) in older thrombotic occlusions, especially since the higher rate of embolization was mainly due to an increased proportion of larger embolic particles (1 mm), which are clinically more significant.

To compare the effectiveness of five basic cerebral protection devices designed for carotid angioplasty in an in-vitro bench-top model.Simulation of embolization from carotid angioplasty (n = 180) was performed with polyvinyl alcohol (PVA) particles (Contour; 150-1,000- micro m) in an open flow model simulating the aortic arch with a carotid bifurcation made from elastic silicone tubes. Particles (150-250 micro m [small], 355-500 micro m [medium], 710-1,000 micro m [large]; 5 mg each) were injected separately into the internal carotid artery (ICA) proximal to the placed protection device. Five devices were tested: the Angioguard (AG), Filter Wire EX (EX(A), EX(B)), Trap, Neuroshield (NS), and GuardWire Plus (GW). Particles getting past the protection device or flowing into the external carotid artery (ECA) were caught in a filter at the end of both arteries and their weight was determined.For small, medium, and large particles, the lowest weight of emboli in the effluent of the ICA was obtained with the NS (0.28 mg, 0.18 mg, and 0.07 mg, respectively; P.001 compared to all other devices except the GW for small particles only). The GW had the highest embolization rate into the ECA for all particle sizes. When combining the particle weights for the different protection devices, the NS showed the lowest weight of emboli into the ICA filter (0.53 mg/3.5%; P.001 compared to all [1.1 mg/7.0%]). The GW revealed the highest weight of emboli into the ECA (1.2 mg/7.6%; P.001 compared to all [0.59 mg/0.09%]). Effectiveness of the EX(B) device was enhanced when circumferentially deployed under direct view (EX(B), 0.39 mg/2.58%; EX(A), 1.18 mg/7.81%; P.001).In vitro, none of the tested devices or modifications has the ability to prevent embolization completely. An occlusion balloon leads to increased embolization into the ECA. The effectiveness of the EX might be enhanced with design improvements. During this evaluation, the NS was most effective for preventing PVA particle embolization of the three different particle groups within this in-vitro model.

Our objective was to compare a water-excitation (WE) 3D fast low-angle shot (FLASH) MR sequence for faster imaging of articular cartilage defects of the knee to a conventional fat-saturated (FS) 3D FLASH MR sequence. This prospective study included 16 knees of 16 patients with suspected cartilage lesions. The MR imaging in transverse and sagittal planes included (a) FS 3D FLASH (TR/TE: 45 ms/11 ms, scan time 8 min, flip angle 50 degrees), and (b) WE 3D FLASH (TR/TE: 28 ms/11 ms, scan time 4 min 58 s, flip angle 40 degrees). For each sequence signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) were quantified. The detected cartilage lesions were evaluated using a semi-quantitative four-scale scoring system (grades 0-III). The data were compared between the sequences using the paired Student's t-test. No statistically significant differences between the sequences were found for SNR, CNR, and cartilage defect grading (p=0.14-0.8). The WE 3D FLASH MR imaging seems to be promising for fast imaging of articular cartilage lesions of the knee.

OBJECTIVE To determine the in vitro effectiveness of the Amplatz and Rotarex catheters for thrombus fragmentation and combined thrombus fragmentation and aspiration. MATERIALS AND METHODS Clots (n = 100) from 5-day-old porcine blood (8.5 g) were fragmented with the 8F Rotarex trade mark catheter (RR; 40.000 rpm), which was directed with or without a coaxial guide wire (GW 0.020 inch [8 F RR(GW)], GW 0.014 inch [6 F RR(GW)]), and with the 7 F Amplatz catheter (ATD; 150.000 rpm), in an artery flow model (pulsed flow of 700 ml/min) simulating the superficial femoral artery. To increase the wall adherence of the thrombus, an additional equal number of silicon tubes (with an inner diameter of 7 mm) were fitted inside with a metallic mesh (wall-adherent thrombus [WAT]; 6 F RR(WAT), 8 F RR(WAT), 6 F R(WAT-GW), 8 F RR(WAT-GW), ATD(WAT) ). The effluent was passed through a three-step filter system (10 to 1000 micro m; pressure gradient 35 mmHg). RESULTS Highest effectiveness was found for 8 F RR (no remaining thrombus detectable) compared to 6 F RR (0.08 g) and ATD (0.07 g), with a p < 0.001 for both methods. The aspirated volume was significantly lower when 6 F and 8 F RR were used with a coaxial guide wire (p < 0.001). The total emboli rate for 8 F RR was significantly lower compared to ATD (p < 0.001). Even when working without a guide wire, 8 F RR caused the lowest proportion of emboli (depending on the modification 0.12 % to 1.76 %; compared to all p < 0.05). Emboli rates reached 7.99 % for 6 F RR (compared to all p < 0.001) and were maximal 5.61 % for ATD. CONCLUSIONS The tested mechanical thrombectomy catheters have a high potential for in vitro thrombectomy with moderate performance differences. In contrast to the guidewire-directed Rotarex fragmentation-aspiration device, the ATD trade mark fragmentation catheter and prototype Rotarex 6 F catheter have a considerable peripheral embolization rate of particles larger than 1000 micro m, probably requiring additional measures for in vivo thrombectomy.

Purpose: To evaluate in an in vitro bench-top model the efficacy of 4 filtration devices designed for cerebral protection during carotid angioplasty. Methods: Embolization during carotid angioplasty was simulated with human plaque material (8 to 12 particles weighing 6.02 ± 0.10 mg) in an open flow model with the aortic arch and carotid bifurcation made from elastic silicone tubes and saline used as the fluid medium. The 500 to 1500-µm particles were injected into the internal carotid artery (ICA) in front of the test protection device, which was deployed 5 cm distal to the bifurcation. Particles getting past the protection device or flowing into the external carotid artery (ECA) were caught in 100-µm filters and weighed. Ten trials were made on each of 4 devices: Angioguard, FilterWire EX, TRAP, and NeuroShield. All were deployed according to the manufacturers' directions except the FilterWire, which was manually repositioned in all tests to eliminate a gap between the filter and the tube wall. Results: The lowest weight of missed particles in the effluent was obtained with the NeuroShield (0.05 ± 0.04 mg, 0.8% of injected particle weight) and FilterWire (0.08 ± 0.05 mg, 1.3%; p=0.254 compared to NeuroShield, p=0.006 versus TRAP). The weight of particles missed by the TRAP device (0.16 ± 0.06 mg, 2.6%; pConclusions: In vitro, none of the tested devices had the ability to completely prevent embolization into the ICA. Comparing current designs, the NeuroShield filter and the FilterWire EX captured the highest percentage of human particles in this in vitro model, probably due to their larger filter volume.

The effectiveness of two basic cerebral protection devices designed for carotid angioplasty with and without additional aspiration techniques was compared in an in vitro model. During carotid angioplasty, embolization was simulated by injecting polyvinyl alcohol particles of different sizes into the model system. None of the tested devices, all of which were positioned in the internal carotid artery, was able to completely prevent embolization. In the internal carotid artery, the rate of particle capture did not vary among protection devices. However, embolization into the external carotid artery was more frequent with use of the GuideWire, as compared with that with use of the Angioguard.

PURPOSE An experimental study using porcine lung explants and a dedicated chest phantom to evaluate the signal intensity of artificial alveolar infiltrates with T 1 - and T 2 -weighted MRI sequences. MATERIAL AND METHODS 10 porcine lung explants were intubated, transferred into the cavity of a MRI-compatible chest phantom and inflated by continuous evacuation of the artificial pleural space. All lungs were examined with MRI at 1.5 T before and after intra-tracheal instillation of either 100 or 200 ml gelatine-stabilised liquid to simulate alveolar infiltrates. MR-examination comprised gradient echo (2D- and 3D-GRE) and fast spin echo sequences (T 2 -TSE and T 2 -HASTE). The signal intensity of lung parenchyma was evaluated at representative cross sections using a standardised scheme. Control studies were acquired with helical CT. RESULTS The instilled liquid caused patchy confluent alveolar infiltrates resembling the findings in patients with pneumonia or ARDS. CT revealed typical ground-glass opacities. Before the application of the liquid, only T 2 -HASTE and T 2 -TSE displayed lung parenchyma signals with a signal/noise ratio of 3.62 and 1.39, respectively. After application of the liquid, both T 2 -weighted sequences showed clearly visible infiltrates with an increase in signal intensity of approx. 30 % at 100 ml (p < 0.01) and 60 % at 200 ml (p < 0.01). With 2D- and 3D-GRE the infiltrates were not visible, although the lung parenchyma signal increase was statistically significant. On 2D-GRE the increase in signal intensity reached 0.74 % (p = 0.32) after 100 ml and 5.6 % (p < 0.01) after 200 ml (for 3D-GRE: 2.2 % [p = 0.02] at 100 ml and 4.4 % at 200 ml [p < 0.01]). The CT controls revealed a significant increase of lung density of 17 H.E. at 100 ml (p = 0.02) and 75 H.E. at 200 ml (p < 0.01). CONCLUSIONS MRI with T 2 -weighted sequences detects artificial alveolar infiltrates with high signal intensity and may be a highly sensitive tool to detect pneumonia in patients.

To determine in vitro the efficacy of clot removal of the AngioJet (AJ; new 6-F generation), Hydrolyser (HL; 6-F), and Oasis (OS; 6-F) hydrodynamic thrombectomy devices and the Amplatz Thrombectomy Device fragmentation catheter (ATD; 8-F and new-generation 7-F) in large-diameter vessels and low-pressure fluid dynamic applications (ie, pulmonary embolism).Thrombectomy of clots (N = 60; n = 12 for each tested device) created from 5-day-old porcine blood (16 g) was performed with the AJ (with coaxial 0.035-inch guide wire), HL, OS, and ATD in a bench-top model simulating low-pressure fluid dynamics (pulsed flow, 1,250 L/min). Tubes made of silicone (20-mm inner diameter) containing thrombus simulated a large-diameter vessel. The effluent was passed through a three-step filter system (10-1,000 micro m; pressure drop, 15 mm Hg).Mean thrombectomy time ranged from 83 seconds (7-F ATD) to 185 seconds (OS; P.0001 compared to all). Remaining thrombus ranged from 5.4 g/32.7% (AJ) to 11.1 g/68.1% (HL; P.001 compared to all). The AJ's fluid balance was 0.92, whereas the mean ratio of applied saline solution to aspirated fluid for the other devices were significantly different than isovolumetric conditions (HL, 0.64; OS, 0.59; P.0001 compared to AJ). The AJ (0.36%), HL (0.43%), and OS (0.38%) caused the least overall emboli larger than 10 micro m; the ATD (7-F, 0.82%; 8-F, 0.74%) caused the most (P.001 for both).The tested mechanical thrombectomy devices showed performance differences in thrombectomy time, efficacy of thrombus removal, and peripheral embolization rates. Based on low embolization rates for all devices tested, the experimental data indicate that the 7-F ATD and the 0.035-inch guide-wire-compatible AJ showed feasibility advantages for thrombectomy in large vessel diameter and low-pressure fluid dynamic applications.

Post-traumatic changes of the alar ligaments have been proposed to be the cause of chronic pain in patients after whiplash injury of the cervical spine. In addition to an asymmetric dens position, widening of the atlantodental distance to more than 12 mm can be an indirect sign of an alar ligament rupture. CT is recommended for detection of a avulsion fracture of the occipital condyle. Isolated ruptures of the alar ligaments are best visualized on MRI. In patients with chronic impairments after whiplash injuries changes of the alar ligaments on MRI must be differentiated from normal variants in healthy individuals.

OBJECTIVE To evaluate the technical feasibility of a new monorail-stent-balloon device for treatment of renal artery stenosis (RAS). PATIENTS AND METHODS During a study period of 18 months, 38 patients with proven RAS in 41 cases (hypertension n = 36, renal insufficiency n = 13) and indication for stenting (calicified ostial lesions n = 35, insufficient PTA n = 4, dissection n = 2) were enrolled into this prospective evaluation. Pre-mounted stents (Rx-Herculink(TM) 5 mm = 13, 6 mm = 34, 7 mm = 1) were implanted a transfemoral (n = 35) or transbrachial approach (n = 6). Mean grade and lengths of stenosis measured were 88 % plus minus 10 and 9 mm plus minus 5. RESULTS Renal stent implantation was technically successful in all cases (100 %). In 7 cases a second stent had to be implanted to cover the entire lesion. The transstenotic pressure drop decreased from 88 mmHg plus minus 10 before to 1 mmHg plus minus 1.8 after the procedure. Remaining stenosis measured 0.7 % plus minus 4.2. Serum creatine levels decreased from 1.9 mm/dl to 1.5 mg/dl (n. s.), blood pressure decreased from 178/94 mmHg to 148/79 mmHg (p < 0.0001) after the intervention. Primary and secondary patency rates at 6 months were 72 % (Standard Error 9.8 %) and 77 (% (Standard Error 9.2 %), respectively. CONCLUSION With the used monorail-stend-balloon device a technically easy, secure and exact renal stent placement is guaranteed, patency rates are similar to those described in the current literature.

To report on a prospective two-center study to evaluate safety and effectiveness of a self-expanding nitinol coil stent in patients with femoropopliteal obstructive disease.The IntraCoil nitinol stent was used in 37 patients (28 men and nine women; mean age, 62.4 y plus minus 10.7; range, 43-81 y) presenting with high-grade stenoses (n = 23) or short (3 cm) occlusions (n = 17) of the superficial femoral artery (SFA; n = 33) or popliteal artery (n = 4). Indications for stent placement were significant residual stenosis (30%) or dissection after angioplasty. Follow-up evaluations with measurement of the Doppler ankle-brachial index (ABI), assessment of Rutherford clinical stage, and color-coded duplex sonography were performed at discharge and 1, 3, 6, 12, and 18 months thereafter. Primary endpoints of the study were immediate technical and clinical success and 1-year patency.Initial technical success was achieved in all patients. In 10 patients (27%), more than one 40-mm-long device had to be implanted for total lesion coverage; in three patients (8.1%), stents were placed in two separate segments of the SFA simultaneously. The total number of stents deployed was 50. Stent placement induced an initial improvement of the ABI from 0.54 plus minus 0.2 to 0.92 plus minus 0.11 (P.01). Follow-up data for 12 months after treatment are available for 29 of 37 patients (78.4%); mean follow-up is 15.6 months (range, 1-26 mo). Primary patency rates at 6 and 12 months were 97.1% (SE = 2.9) and 86.2% (SE = 6.5). The primary assisted patency rate was 100% at 12 months.Endovascular placement of the IntraCoil self-expanding nitinol coil stent for salvage of failed angioplasty in patients with femoropopliteal obstructive disease is an effective and safe procedure with promising mid-term results.

Nanoparticles are frequently suggested as diagnostic agents. However, except for iron oxide nanoparticles, diagnostic nanoparticles have been barely incorporated into clinical use so far. This is predominantly due to difficulties in achieving acceptable pharmacokinetic properties and reproducible particle uniformity as well as to concerns about toxicity, biodegradation, and elimination. Reasonable indications for the clinical utilization of nanoparticles should consider their biologic behavior. For example, many nanoparticles are taken up by macrophages and accumulate in macrophage-rich tissues. Thus, they can be used to provide contrast in liver, spleen, lymph nodes, and inflammatory lesions (eg, atherosclerotic plaques). Furthermore, cells can be efficiently labeled with nanoparticles, enabling the localization of implanted (stem) cells and tissue-engineered grafts as well as in vivo migration studies of cells. The potential of using nanoparticles for molecular imaging is compromised because their pharmacokinetic properties are difficult to control. Ideal targets for nanoparticles are localized on the endothelial luminal surface, whereas targeted nanoparticle delivery to extravascular structures is often limited and difficult to separate from an underlying enhanced permeability and retention (EPR) effect. The majority of clinically used nanoparticle-based drug delivery systems are based on the EPR effect, and, for their more personalized use, imaging markers can be incorporated to monitor biodistribution, target site accumulation, drug release, and treatment efficacy. In conclusion, although nanoparticles are not always the right choice for molecular imaging (because smaller or larger molecules might provide more specific information), there are other diagnostic and theranostic applications for which nanoparticles hold substantial clinical potential.