Heike Daldrup-Link

All Publications

• Tracking Stem Cell Implants in Cartilage Defects of Minipigs by Using Ferumoxytol-enhanced MRI. Radiology Theruvath, A. J., Nejadnik, H., Lenkov, O., Yerneni, K., Li, K., Kuntz, L., Wolterman, C., Tuebel, J., Burgkart, R., Liang, T., Felt, S., Daldrup-Link, H. E. 2019: 182176

  Abstract

  Background Cartilage repair outcomes of matrix-associated stem cell implants (MASIs) in patients have been highly variable. Conventional MRI cannot help distinguish between grafts that will and grafts that will not repair the underlying cartilage defect until many months after the repair. Purpose To determine if ferumoxytol nanoparticle labeling could be used to depict successful or failed MASIs compared with conventional MRI in a large-animal model. Materials and Methods Between January 2016 and December 2017, 10 Gottingen minipigs (n = 5 male; n = 5 female; mean age, 6 months ± 5.1; age range, 4-20 months) received implants of unlabeled (n = 12) or ferumoxytol-labeled (n = 20) viable and apoptotic MASIs in cartilage defects of the distal femur. All MASIs were serially imaged with MRI on a 3.0-T imaging unit at week 1 and weeks 2, 4, 8, 12, and 24, with calculation of T2 relaxation times. Cartilage regeneration outcomes were assessed by using the MR observation of cartilage repair tissue (MOCART) score (scale, 0-100), the Pineda score, and histopathologic quantification of collagen 2 production in the cartilage defect. Findings were compared by using the unpaired Wilcoxon rank sum test, a linear regression model, the Fisher exact test, and Pearson correlation. Results Ferumoxytol-labeled MASIs showed significant T2 shortening (22.2 msec ± 3.2 vs 27.9 msec ± 1.8; P < .001) and no difference in cartilage repair outcomes compared with unlabeled control MASIs (P > .05). At week 2 after implantation, ferumoxytol-labeled apoptotic MASIs showed a loss of iron signal and higher T2 relaxation times compared with ferumoxytol-labeled viable MASIs (26.6 msec ± 4.9 vs 20.8 msec ± 5.3; P = .001). Standard MRI showed incomplete cartilage defect repair of apoptotic MASIs at 24 weeks. Iron signal loss at 2 weeks correlated with incomplete cartilage repair, diagnosed at histopathologic examination at 12-24 weeks. Conclusion Ferumoxytol nanoparticle labeling can accelerate the diagnosis of successful and failed matrix-associated stem cell implants at MRI in a large-animal model. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Sneag and Potter in this issue.

  View details for PubMedID 31063081

• Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation. Clinical cancer research : an official journal of the American Association for Cancer Research Aghighi, M., Theruvath, A. J., Pareek, A., Pisani, L., Alford, R., Muehe, A. M., Sethi, T. K., Holdsworth, S. J., Hazard, F. K., Gratzinger, D., Luna-Fineman, S., Advani, R. H., Spunt, S. L., Daldrup-Link, H. E. 2018

  Abstract

  Tumor associated macrophages (TAM) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with non-invasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.In a first-in-patient, IRB-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (2 lymphoma, 3 bone sarcoma) underwent pre- and post-contrast MRI. Subsequently, 20 patients (10 lymphoma, 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24-48 hours after intravenous injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol-MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Significant ferumoxytol tumor enhancement was noted on post-contrast scans compared to pre-contrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies.

  View details for PubMedID 29764855

• A novel theranostic strategy for MMP-14 expressing glioblastomas impacts survival. Molecular cancer therapeutics Mohanty, S., Chen, Z., Li, K., Morais, G. R., Klockow, J., Yerneni, K., Pisani, L., Chin, F. T., Mitra, S., Cheshier, S., Chang, E., Gambhir, S. S., Rao, J., Loadman, P. M., Falconer, R. A., Daldrup-Link, H. E. 2017

  Abstract

  Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of MMP-14 expressing GBM, induced GIC apoptosis and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled in vivo drug tracking with MR imaging. Treatment with CLIO-ICT plus temozolomide achieved tumor remission and significantly increased survival of human GBM bearing mice by more than 2 fold compared to treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation.

  View details for PubMedID 28659432

• A PET/MR Imaging Approach for the Integrated Assessment of Chemotherapy-induced Brain, Heart, and Bone Injuries in Pediatric Cancer Survivors: A Pilot Study. Radiology Theruvath, A. J., Ilivitzki, A., Muehe, A., Theruvath, J., Gulaka, P., Kim, C., Luna-Fineman, S., Sakamoto, K. M., Yeom, K. W., Yang, P., Moseley, M., Chan, F., Daldrup-Link, H. E. 2017: 170073

  Abstract

  Purpose To develop a positron emission tomography (PET)/magnetic resonance (MR) imaging protocol for evaluation of the brain, heart, and joints of pediatric cancer survivors for chemotherapy-induced injuries in one session. Materials and Methods Three teams of experts in neuroimaging, cardiac imaging, and bone imaging were tasked to develop a 20-30-minute PET/MR imaging protocol for detection of chemotherapy-induced tissue injuries of the brain, heart, and bone. In an institutional review board-approved, HIPAA-compliant, prospective study from April to July 2016, 10 pediatric cancer survivors who completed chemotherapy underwent imaging of the brain, heart, and bone with a 3-T PET/MR imager. Cumulative chemotherapy doses and clinical symptoms were correlated with the severity of MR imaging abnormalities by using linear regression analyses. MR imaging measures of brain perfusion and metabolism were compared among eight patients who were treated with methotrexate and eight untreated age-matched control subjects by using Wilcoxon rank-sum tests. Results Combined brain, heart, and bone examinations were completed within 90 minutes. Eight of 10 cancer survivors had abnormal findings on brain, heart, and bone images, including six patients with and two patients without clinical symptoms. Cumulative chemotherapy doses correlated significantly with MR imaging measures of left ventricular ejection fraction and end-systolic volume, but not with the severity of brain or bone abnormalities. Methotrexate-treated cancer survivors had significantly lower cerebral blood flow and metabolic activity in key brain areas compared with control subjects. Conclusion The feasibility of a single examination for assessment of chemotherapy-induced injuries of the brain, heart, and joints was shown. Earlier detection of tissue injuries may enable initiation of timely interventions and help to preserve long-term health of pediatric cancer survivors. (©) RSNA, 2017 Online supplemental material is available for this article.

  View details for PubMedID 28777701

• How to Provide Gadolinium-Free PET/MR Cancer Staging of Children and Young Adults in Less than 1 h: the Stanford Approach. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Muehe, A. M., Theruvath, A. J., Lai, L., Aghighi, M., Quon, A., Holdsworth, S. J., Wang, J., Luna-Fineman, S., Marina, N., Advani, R., Rosenberg, J., Daldrup-Link, H. E. 2017

  Abstract

  To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h.In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [(18)F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests.Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [(18)F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %).Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.

  View details for PubMedID 28721605

• Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nature nanotechnology Zanganeh, S., Hutter, G., Spitler, R., Lenkov, O., Mahmoudi, M., Shaw, A., Pajarinen, J. S., Nejadnik, H., Goodman, S., Moseley, M., Coussens, L. M., Daldrup-Link, H. E. 2016; 11 (11): 986-994

  Abstract

  Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. Here, we show an intrinsic therapeutic effect of ferumoxytol on the growth of early mammary cancers, and lung cancer metastases in liver and lungs. In vitro, adenocarcinoma cells co-incubated with ferumoxytol and macrophages showed increased caspase-3 activity. Macrophages exposed to ferumoxytol displayed increased mRNA associated with pro-inflammatory Th1-type responses. In vivo, ferumoxytol significantly inhibited growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol treatment before intravenous tumour cell challenge prevented development of liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology studies showed that the observed tumour growth inhibition was accompanied by increased presence of pro-inflammatory M1 macrophages in the tumour tissues. Our results suggest that ferumoxytol could be applied 'off label' to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.

  View details for DOI 10.1038/nnano.2016.168

  View details for PubMedID 27668795

• Ionising radiation-free whole-body MRI versus (18)F-fluorodeoxyglucose PET/CT scans for children and young adults with cancer: a prospective, non-randomised, single-centre study. lancet oncology Klenk, C., Gawande, R., Uslu, L., Khurana, A., Qiu, D., Quon, A., Donig, J., Rosenberg, J., Luna-Fineman, S., Moseley, M., Daldrup-Link, H. E. 2014; 15 (3): 275-285

  Abstract

  Imaging tests are essential for staging of children with cancer. However, CT and radiotracer-based imaging procedures are associated with substantial exposure to ionising radiation and risk of secondary cancer development later in life. Our aim was to create a highly effective, clinically feasible, ionising radiation-free staging method based on whole-body diffusion-weighted MRI and the iron supplement ferumoxytol, used off-label as a contrast agent.We compared whole-body diffusion-weighted MRI with standard clinical (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT scans in children and young adults with malignant lymphomas and sarcomas. Whole-body diffusion-weighted magnetic resonance images were generated by coregistration of colour-encoded ferumoxytol-enhanced whole-body diffusion-weighted MRI scans for tumour detection with ferumoxytol-enhanced T1-weighted MRI scans for anatomical orientation, similar to the concept of integrated (18)F-FDG PET/CT scans. Tumour staging results were compared using Cohen's κ statistics. Histopathology and follow-up imaging served as the standard of reference. Data was assessed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01542879.22 of 23 recruited patients were analysed because one patient discontinued before completion of the whole-body scan. Mean exposure to ionising radiation was 12·5 mSv (SD 4·1) for (18)F-FDG PET/CT compared with zero for whole-body diffusion-weighted MRI. (18)F-FDG PET/CT detected 163 of 174 malignant lesions at 1325 anatomical regions and whole-body diffusion-weighted MRI detected 158. Comparing (18)F-FDG PET/CT to whole-body diffusion-weighted MRI, sensitivities were 93·7% (95% CI 89·0-96·8) versus 90·8% (85·5-94·7); specificities 97·7% (95% CI 96·7-98·5) versus 99·5% (98·9-99·8); and diagnostic accuracies 97·2% (93·6-99·4) versus 98·3% (97·4-99·2). Tumour staging results showed very good agreement between both imaging modalities with a κ of 0·93 (0·81-1·00). No adverse events after administration of ferumoxytol were recorded.Ferumoxytol-enhanced whole-body diffusion-weighted MRI could be an alternative to (18)F-FDG PET/CT for staging of children and young adults with cancer that is free of ionising radiation. This new imaging test might help to prevent long-term side-effects from radiographic staging procedures.Thrasher Research Fund and Clinical Health Research Institute at Stanford University.

  View details for DOI 10.1016/S1470-2045(14)70021-X

  View details for PubMedID 24559803

• Rethinking Brain Cancer Therapy: Tumor Enzyme Activatable Theranostic Nanoparticles. Molecular imaging Daldrup-Link, H. E. ; 16: 1536012117730950

  Abstract

  This invited commentary discusses a recent article by Mohanty et al in Molecular Cancer Therapeutics about significant therapeutic efficacies of novel theranostic nanoparticles (TNPs) for the treatment of human brain cancers in mouse models. The TNPs were cleaved by enzymes in the tumor tissue, matrix metalloproteinase (MMP-14), which lead to release of a highly potent therapeutic drug, azademethylcolchicine. Data showed that the TNPs caused selective toxic effects in MMP-14-expressing glioblastoma and not normal brain. In addition, the iron oxide nanoparticle backbone enabled in vivo drug tracking with magnetic resonance imaging (MRI). This commentary discusses previous efforts of MMP-targeted therapeutics as well as opportunities for further refinements of tumor enzyme-activatable TNPs. If successfully translated to clinical applications, the TNPs might hold substantial potential to improving cytotoxic indexes and long-term outcomes of patients with brain cancer compared to standard therapy.

  View details for PubMedID 28929923

• Vom Rontgen zum PET/MRT, und dann? - Zukunftsweisende Bildgebung in der Kinderradiologie. RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin Staatz, G., Daldrup-Link, H. E., Herrmann, J., Hirsch, F. W., Schafer, J. F., Seehofnerova, A., Sorantin, E., Theruvath, A. J., Lollert, A. 2019; 191 (4): 357–66

  Abstract

  Significant changes can be expected in modern pediatric radiology. New imaging techniques are progressively added to basic modalities like Xrays and ultrasound. This essay summarizes recent advances and technical innovations in pediatric radiology, which are supposed to gain further importance in the future. Thus, CT dose reduction techniques including artificial intelligence as well as advances in the fields of magnetic resonance and molecular imaging are presented. KEY POINTS: · Technical innovations will lead to significant changes in pediatric radiology.. · CT dose reduction is crucial for pediatric patient collectives.. · New MR-techniques will lower the need for sedation and contrast media application.. · Functional MR-imaging might gain further importance in patients with chronic lung disease.. · Molecular imaging enables detection, characterization and quantification of molecular processes in tumors.. CITATION FORMAT: · Staatz G, Daldrup-Link HE, Herrmann J et al. From Xrays to PET/MR, and then? - Future imaging in pediatric radiology. Fortschr Rontgenstr 2019; 191: 357 - 366.

  View details for PubMedID 30897652

• Magnetic resonance imaging of stem cell-macrophage interactions with ferumoxytol and ferumoxytol-derived nanoparticles. Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology Nejadnik, H., Tseng, J., Daldrup-Link, H. 2019: e1552

  Abstract

  "Off the shelf" allogeneic stem cell transplants and stem cell nano-composites are being used for the treatment of degenerative bone diseases. However, major and minor histocompatibility antigens of therapeutic cell transplants can be recognized as foreign and lead to their rejection by the host immune system. If a host immune response is identified within the first week post-transplant, immune modulating therapies could be applied to prevent graft failure and support engraftment. Ferumoxytol (Feraheme) is an FDA approved iron oxide nanoparticle preparation for the treatment of anemia in patients. Ferumoxytol can be used "off label" as an magnetic resonance (MR) contrast agent, as these nanoparticles provide measurable signal changes on magnetic resonance imaging (MRI). In this focused review article, we will discuss three methods to localize and identify innate immune responses to stem cell transplants using ferumoxytol-enhanced MRI, which are based on tracking stem cells, tracking macrophages or detecting mediators of cell death: (a) monitor MRI signal changes of ferumoxytol-labeled stem cells in the presence or absence of innate immune responses, (b) monitor influx of ferumoxytol-labeled macrophages into stem cell implants, and (c) monitor apoptosis of stem cell implants with caspase-3 activatable nanoparticles. These techniques can detect transplant failure at an early stage, when immune-modulating interventions can potentially preserve the viability of the cell transplants and thereby improve bone and cartilage repair outcomes. Approaches 1 and 2 are immediately translatable to clinical practice. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > Biosensing.

  View details for PubMedID 30734542

• Nanoparticle enhanced MRI can monitor macrophage response to CD47 mAb immunotherapy in osteosarcoma. Cell death & disease Mohanty, S., Yerneni, K., Theruvath, J. L., Graef, C. M., Nejadnik, H., Lenkov, O., Pisani, L., Rosenberg, J., Mitra, S., Cordero, A. S., Cheshier, S., Daldrup-Link, H. E. 2019; 10 (2): 36

  Abstract

  CD47 monoclonal antibodies (mAbs) activate tumor-associated macrophages (TAMs) in sarcomas to phagocytose and eliminate cancer cells. Though CD47 mAbs have entered clinical trials, diagnostic tests for monitoring therapy response in vivoare currently lacking. Ferumoxytol is an FDA-approved iron supplement which can be used "off label" as a contrast agent: the nanoparticle-based drug is phagocytosed by TAM and can be detected with magnetic resonance imaging (MRI). We evaluated if ferumoxytol-enhanced MRI can monitor TAM response to CD47 mAb therapy in osteosarcomas. Forty-eight osteosarcoma-bearing mice were treated with CD47 mAb or control IgG and underwent pre- and post-treatment ferumoxytol-MRI scans. Tumor enhancement, quantified as T2 relaxation times, was compared with the quantity of TAMs as determined by immunofluorescence microscopy and flow cytometry. Quantitative data were compared between experimental groups using exact two-sided Wilcoxon rank-sum tests. Compared to IgG-treated controls, CD47 mAb-treated tumors demonstrated significantly shortened T2 relaxation times on ferumoxytol-MRI scans (p<0.01) and significantly increased F4/80+CD80+ M1 macrophages on histopathology (p<0.01). CD47 mAb-treated F4/80+ macrophages demonstrated significantly augmented phagocytosis of ferumoxytol nanoparticles (p<0.01). Thus, we conclude that ferumoxytol-MRI can detect TAM response to CD47 mAb in mouse models of osteosarcoma. The ferumoxytol-MRI imaging test could be immediately applied to monitor CD47 mAb therapies in clinical trials.

  View details for PubMedID 30674867

• Investigating macrophage-mediated inflammation in migraine using ultrasmall superparamagnetic iron oxide-enhanced 3T magnetic resonance imaging. Cephalalgia : an international journal of headache Khan, S., Mohammad Amin, F., Petrine Fliedner, F., Emil Christensen, C., Tolnai, D., Younis, S., Christine Rye Olinger, A., Birgens, H., Daldrup-Link, H., Kjær, A., Larsson, H. B., Lindberg, U., Ashina, M. 2019: 333102419848122

  Abstract

  Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology.We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine.Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898.A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side.Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.

  View details for DOI 10.1177/0333102419848122

  View details for PubMedID 31104505

• Clinical Tracking of Cell Transfer and Cell Transplantation: Trials and Tribulations. Radiology Bulte, J. W., Daldrup-Link, H. E. 2018: 180449

  Abstract

  Cell therapy has provided unprecedented opportunities for tissue repair and cancer therapy. Imaging tools for in vivo tracking of therapeutic cells have entered the clinic to evaluate therapeutic cell delivery and retention in patients. Thus far, clinical cell tracking studies have been a mere proof of principle of the feasibility of cell detection. This review centers around the main clinical queries associated with cell therapy: Have cells been delivered correctly at the targeted site of injection? Are cells still alive, and, if so, how many? Are cells being rejected by the host, and, if so, how severe is the immune response? For stem cell therapeutics, have cells differentiated into downstream cell lineages? Is there cell proliferation including tumor formation? At present, clinical cell tracking trials have only provided information on immediate cell delivery and short-term cell retention. The next big question is if these cell tracking tools can improve the clinical management of the patients and, if so, by how much, for how many, and for whom; in addition, it must be determined whether tracking therapeutic cells in every patient is needed. To become clinically relevant, it must now be demonstrated how cell tracking techniques can inform patient treatment and affect clinical outcomes.

  View details for PubMedID 30299232

• Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof of Concept Study in Patients. Clinical cancer research : an official journal of the American Association for Cancer Research Theruvath, A. J., Nejadnik, H., Muehe, A. M., Gassert, F., Lacayo, N. J., Goodman, S. B., Daldrup-Link, H. E. 2018

  Abstract

  PURPOSE: Osteonecrosis (ON) is a devastating complication of high dose corticosteroid therapy in cancer patients. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in ON lesions.EXPERIMENTAL DESIGN: In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MR imaging studies of nine hip joints of seven ON patients before and after core decompression. 24-48hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron labeled bone marrow cells were aspirated from the iliac crest, concentrated and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation.RESULTS: Iron labeled cells could be detected in the access canal by a dark (negative) signal on T2*-weighted MR images. T2* relaxation times of iron labeled cell transplants were significantly lower compared to unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair.CONCLUSIONS: This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.

  View details for PubMedID 30224340

• Ferumoxytol Can Be Used for Quantitative Magnetic Particle Imaging of Transplanted Stem Cells. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Nejadnik, H., Pandit, P., Lenkov, O., Lahiji, A. P., Yerneni, K., Daldrup-Link, H. E. 2018

  Abstract

  PURPOSE: To evaluate, if clinically translatable ferumoxytol nanoparticles can be used for in vivo detection and quantification of stem cell transplants with magnetic particle imaging (MPI).PROCEDURES: Mesenchymal stem cells (MSCs) were labeled with ferumoxytol or ferucarbotran and underwent MPI, magnetic resonance imaging (MRI), Prussian blue staining, and inductively coupled plasma (ICP) spectrometry. Unlabeled, ferumoxytol, and ferucarbotran-labeled MSCs were implanted in calvarial defects of eight mice and underwent MPI, MRI, and histopathology. The iron concentration calculated according to the MPI signal intensity and T2 relaxation times of the three different groups were compared using an analysis of variance (ANOVA) with Bonferroni correction, and a p<0.05.RESULTS: Compared to unlabeled controls, ferumoxytol- and ferucarbotran-labeled MSC showed significantly increased iron content, MPI signal and MRI signal. The ferumoxytol MPI signal was approximately 4* weaker compared to ferucarbotran at equimolar concentrations (p=0.0003) and approximately 1.5* weaker for labeled cells when using optimized labeling protocols (p=0.002). In vivo, the MPI signal of ferumoxytol-labeled MSC decreased significantly between day 1 and day 14 (p=0.0124). This was confirmed by histopathology where we observed a decrease in Prussian blue stain of MSCs at the transplant site. The MRI signal of the same transplants did not change significantly during this observation period (p=0.93).CONCLUSION: Ferumoxytol nanoparticles can be used for in vivo detection of stem cell transplants with MPI and provide quantitative information not attainable with MRI.

  View details for PubMedID 30194566

• Variability in billing practices for whole-body magnetic resonance imaging: reply to Degnan et al. Pediatric radiology Schooler, G. R., Davis, J. T., Daldrup-Link, H., Frush, D. P. 2018

  View details for PubMedID 30191257

• Association of Tumor [18F]FDG Activity and Diffusion Restriction with Clinical Outcomes of Rhabdomyosarcomas. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Pourmehdi Lahiji, A., Jackson, T., Nejadnik, H., von Eyben, R., Rubin, D., Spunt, S. L., Quon, A., Daldrup-Link, H. 2018

  Abstract

  PURPOSE: To evaluate whether the extent of restricted diffusion and 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) uptake of pediatric rhabdomyosarcomas (RMS) on positron emission tomography (PET)/magnetic resonance (MR) images provides prognostic information.PROCEDURE: In a retrospective, IRB-approved study, we evaluated [18F]FDG PET/CT and diffusion-weighted (DW) MR imaging studies of 21 children and adolescents (age 1-20years) with RMS of the head and neck. [18F]FDG PET and DW MR scans at the time of the initial tumor diagnosis were fused using MIM software. Quantitative measures of the tumor mass with restricted diffusion, [18F]FDG hypermetabolism, or both were dichotomized at the median and tested for significance using Gray's test. Data were analyzed using a survival analysis and competing risk model with death as the competing risk.RESULTS: [18F]FDG PET/MR images demonstrated a mismatch between tumor areas with increased [18F]FDG uptake and restricted diffusion. The DWI, PET, and DWI+PET tumor volumes were dichotomized at their median values, 23.7, 16.4, and 9.5cm3, respectively, and were used to estimate survival. DWI, PET, and DWI+PET overlap tumor volumes above the cutoff values were associated with tumor recurrence, regardless of post therapy COG stage (p=0.007, p=0.04, and p=0.07, respectively).CONCLUSION: The extent of restricted diffusion within RMS and overlap of hypermetabolism plus restricted diffusion predict unfavorable clinical outcomes.

  View details for PubMedID 30187233

• Neurovascular Unit: Basic and Clinical Imaging with Emphasis on Advantages of Ferumoxytol NEUROSURGERY Netto, J., Iliff, J., Stanimirovic, D., Krohn, K. A., Hamilton, B., Varallyay, C., Gahramanov, S., Daldrup-Link, H., d'Esterre, C., Zlokovic, B., Sair, H., Lee, Y., Taheri, S., Jain, R., Panigrahy, A., Reich, D. S., Drewes, L. R., Castillo, M., Neuwelt, E. A. 2018; 82 (6): 770–80

  Abstract

  Physiological and pathological processes that increase or decrease the central nervous system's need for nutrients and oxygen via changes in local blood supply act primarily at the level of the neurovascular unit (NVU). The NVU consists of endothelial cells, associated blood-brain barrier tight junctions, basal lamina, pericytes, and parenchymal cells, including astrocytes, neurons, and interneurons. Knowledge of the NVU is essential for interpretation of central nervous system physiology and pathology as revealed by conventional and advanced imaging techniques. This article reviews current strategies for interrogating the NVU, focusing on vascular permeability, blood volume, and functional imaging, as assessed by ferumoxytol an iron oxide nanoparticle.

  View details for PubMedID 28973554

• Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study. Radiology Iv, M., Samghabadi, P., Holdsworth, S., Gentles, A., Rezaii, P., Harsh, G., Li, G., Thomas, R., Moseley, M., Daldrup-Link, H. E., Vogel, H., Wintermark, M., Cheshier, S., Yeom, K. W. 2018: 181204

  Abstract

  Purpose To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. Materials and Methods In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400× magnification high-power fields with iron-containing macrophages. Results Ten adults (four male participants [mean age, 65 years ± 9 {standard deviation}; age range, 57-74 years] and six female participants [mean age, 53 years ± 12 years; age range, 32-65 years]; mean age of all participants, 58 years ± 12 [age range, 32-74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2' and the number of high-power fields with CD163-positive (r range, 0.64-0.71; P < .01) and CD68-positive (r range, 0.55-0.57; P value range, .01-.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein-positive tumor cells. Conclusion MRI measurements of susceptibility, R2*, and R2' (R2* - R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. © RSNA, 2018 Online supplemental material is available for this article.

  View details for PubMedID 30398435

• Writing a review article - Are you making these mistakes? Nanotheranostics Daldrup-Link, H. E. 2018; 2 (2): 197–200

  Abstract

  An explosion of scientific publications over the last decades has increased the need for review articles: Carefully crafted scientific review articles can provide the novice reader with an overview of a new subject and provide the expert with a synthesis of scientific evidence, proof of reproducibility of published data and pooled estimates of common truth through meta-analyses. Unfortunately, while there are ample presentations and published guidelines for the preparation of scientific articles available, detailed information about how to properly prepare scientific review articles is relatively scarce. This perspective summarizes possible mistakes that can lead to misinformation in scientific review articles with the goal to help authors to improve the scientific contribution of their review article and thereby, increase the respective value of these articles for the scientific community.

  View details for PubMedID 29577022

• Ferumoxytol-based Dual-modality Imaging Probe for Detection of Stem Cell Transplant Rejection. Nanotheranostics Li, K., Chan, C. T., Nejadnik, H., Lenkov, O. D., Wolterman, C., Paulmurugan, R., Yang, H., Gambhir, S. S., Daldrup-Link, H. E. 2018; 2 (4): 306–19

  Abstract

  Purpose: Stem cell transplants are an effective approach to repair large bone defects. However, comprehensive techniques to monitor the fate of transplanted stem cells in vivo are lacking. Such strategies would enable corrective interventions at an early stage and greatly benefit the development of more successful tissue regeneration approaches. In this study, we designed and synthesized a dual-modality imaging probe (Feru-AFC) that can simultaneously localize transplanted stem cells and diagnose immune rejection-induced apoptosis at an early stage in vivo. Methods: We used a customized caspase-3 cleavable peptide-dye conjugate to modify the surface of clinically approved ferumoxytol nanoparticles (NPs) to generate the dual-modality imaging probe with fluorescence "light-up" feature. We labeled both mouse mesenchymal stem cells (mMSCs, matched) and pig mesenchymal stem cells (pMSCs, mismatched) with the probe and transplanted the labeled cells with biocompatible scaffold at the calvarial defects in mice. We then employed intravital microscopy (IVM) and magnetic resonance imaging (MRI) to investigate the localization, engraftment, and viability of matched and mismatched stem cells, followed by histological analyses to evaluate the results obtained from in vivo studies. Results: The Feru-AFC NPs showed good cellular uptake efficiency in the presence of lipofectin without cytotoxicity to mMSCs and pMSCs. The fluorescence of Feru-AFC NPs was turned on inside apoptotic cells due to the cleavage of peptide by activated caspase-3 and subsequent release of fluorescence dye molecules. Upon transplantation at the calvarial defects in mice, the intense fluorescence from the cleaved Feru-AFC NPs in apoptotic pMSCs was observed with a concomitant decrease in the overall cell number from days 1 to 6. In contrast, the Feru-AFC NP-treated mMSCs exhibited minimum fluorescence and the cell number also remained similar. Furthermore, in vivo MRI of the Feru-AFC NP-treated mMSC and pMSCs transplants could clearly indicate the localization of matched and mismatched cells, respectively. Conclusions: We successfully developed a dual-modality imaging probe for evaluation of the localization and viability of transplanted stem cells in mouse calvarial defects. Using ferumoxytol NPs as the platform, our Feru-AFC NPs are superparamagnetic and display a fluorescence "light-up" signature upon exposure to activated caspase-3. The results show that the probe is a promising tool for long-term stem cell tracking through MRI and early diagnosis of immune rejection-induced apoptosis through longitudinal fluorescence imaging.

  View details for DOI 10.7150/ntno.26389

  View details for PubMedID 29977742

  View details for PubMedCentralID PMC6030766

• Current utilization and procedural practices in pediatric whole-body MRI. Pediatric radiology Schooler, G. R., Davis, J. T., Daldrup-Link, H. E., Frush, D. P. 2018

  Abstract

  Whole-body magnetic resonance imaging (MRI) is an evolving and increasingly powerful imaging tool with a variety of applications in the pediatric patient population. Variability exists among radiology practices in how this MRI tool is used and how it performed.Our objective was to gain an improved understanding of technical and utilization practices in pediatric whole-body MRI across North America by exploring indications for exam performance, determining referral patterns, and assessing technical protocols and procedures.A 19-question survey was generated in Survey Monkey and distributed in 2016 to the Society for Pediatric Radiology membership. The survey asked questions that included practice type, imaging modality preferences for diseases commonly evaluated with whole-body MRI, MRI field strength and sequence selection, and billing practices.Data were obtained from 62 unique responses to the survey, representing 471 physicians. The majority (93%) practice in an academic institution or private practice with academic affiliation and most practices have utilized whole-body MRI for less than 6 years. Whole-body MRI is performed in pediatric patients 0 to 18 years of age, and was the preferred imaging modality for diagnosis/staging/follow-up in neurofibromatosis, type 1 (75%), chronic recurrent multifocal osteomyelitis (CRMO) (74%), cancer predisposition syndromes (75%), vasculopathies (50%) and disseminated/multifocal infection (49%). The most commonly utilized sequences are coronal short tau inversion recovery (STIR) (90%), coronal T1 with or without fat saturation (65%), and axial diffusion-weighted imaging (DWI) (48%). No preference was shown for either 1.5-T or 3-T systems. Wide variability was seen in preference for billing code utilization, though the majority use chest/abdomen/pelvis (57%) or unlisted MRI (37%) codes.Radiology practitioners - represented by the Society for Pediatric Radiology pediatric radiologists - are using whole-body MRI in the imaging care of pediatric patients for a variety of indications. Survey results reveal some variability in exam utilization and technical performance practices among those pediatric radiologists who perform whole-body MRI.

  View details for PubMedID 29721598

• Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Chapelin, F., Khurana, A., Moneeb, M., Gray Hazard, F. K., Chan, C. F., Nejadnik, H., Gratzinger, D., Messing, S., Erdmann, J., Gaur, A., Daldrup-Link, H. E. 2018

  Abstract

  While imaging matrix-associated stem cell transplants aimed for cartilage repair in a rodent arthritis model, we noticed that some transplants formed locally destructive tumors. The purpose of this study was to determine the cause for this tumor formation in order to avoid this complication for future transplants.Adipose-derived stem cells (ADSC) isolated from subcutaneous adipose tissue were implanted into 24 osteochondral defects of the distal femur in ten athymic rats and two immunocompetent control rats. All transplants underwent serial magnetic resonance imaging (MRI) up to 6 weeks post-transplantation to monitor joint defect repair. Nine transplants showed an increasing size over time that caused local bone destruction (group 1), while 11 transplants in athymic rats (group 2) and 4 transplants in immunocompetent rats did not. We compared the ADSC implant size and growth rate on MR images, macroscopic features, histopathologic features, surface markers, and karyotypes of these presumed neoplastic transplants with non-neoplastic ADSC transplants.Implants in group 1 showed a significantly increased two-dimensional area at week 2 (p = 0.0092), 4 (p = 0.003), and 6 (p = 0.0205) compared to week 0, as determined by MRI. Histopathological correlations confirmed neoplastic features in group 1 with significantly increased size, cellularity, mitoses, and cytological atypia compared to group 2. Six transplants in group 1 were identified as malignant chondrosarcomas and three transplants as fibromyxoid sarcomas. Transplants in group 2 and immunocompetent controls exhibited normal cartilage features. Both groups showed a normal ADSC phenotype; however, neoplastic ADSC demonstrated a mixed population of diploid and tetraploid cells without genetic imbalance.ADSC transplants can form tumors in vivo. Preventive actions to avoid in vivo tumor formations may include karyotyping of culture-expanded ADSC before transplantation. In addition, serial imaging of ADSC transplants in vivo may enable early detection of abnormally proliferating cell transplants.

  View details for PubMedID 29869062

• Transfer learning on fused multiparametric MR images for classifying histopathological subtypes of rhabdomyosarcoma. Computerized medical imaging and graphics Banerjee, I., Crawley, A., Bhethanabotla, M., Daldrup-Link, H. E., Rubin, D. L. 2017

  Abstract

  This paper presents a deep-learning-based CADx for the differential diagnosis of embryonal (ERMS) and alveolar (ARMS) subtypes of rhabdomysarcoma (RMS) solely by analyzing multiparametric MR images. We formulated an automated pipeline that creates a comprehensive representation of tumor by performing a fusion of diffusion-weighted MR scans (DWI) and gadolinium chelate-enhanced T1-weighted MR scans (MRI). Finally, we adapted transfer learning approach where a pre-trained deep convolutional neural network has been fine-tuned based on the fused images for performing classification of the two RMS subtypes. We achieved 85% cross validation prediction accuracy from the fine-tuned deep CNN model. Our system can be exploited to provide a fast, efficient and reproducible diagnosis of RMS subtypes with less human interaction. The framework offers an efficient integration between advanced image processing methods and cutting-edge deep learning techniques which can be extended to deal with other clinical domains that involve multimodal imaging for disease diagnosis.

  View details for DOI 10.1016/j.compmedimag.2017.05.002

  View details for PubMedID 28515009

• Next-generation superparamagnetic iron oxide nanoparticles for cancer theranostics. Drug discovery today Li, K., Nejadnik, H., Daldrup-Link, H. E. 2017

  Abstract

  Superparamagnetic iron oxide (SPIO) nanoparticles have been intensively studied for the development of contrast agents in MRI[SB1] . First-generation SPIO nanoparticles had diagnostic capabilities only, whereas a new generation of SPIO nanoparticle has multifunctional characteristics for combined therapeutic and diagnostic applications. These theranostic nanoparticles hold great potential for image-guided cancer therapies. In particular, polymer-coated theranostic SPIO nanoparticles have enjoyed increasing attention as a result of good biocompatibility, biodegradability and versatile functionality endowed by polymeric matrices. This review provides an overview of recently developed polymer-coated multifunctional SPIO nanoparticles for cancer theranostics and discusses current challenges and future perspectives.

  View details for DOI 10.1016/j.drudis.2017.04.008

  View details for PubMedID 28454771

• Ferumoxytol Is Not Retained in Kidney Allografts in Patients Undergoing Acute Rejection. Molecular imaging and biology Aghighi, M., Pisani, L., Theruvath, A. J., Muehe, A. M., Donig, J., Khan, R., Holdsworth, S. J., Kambham, N., Concepcion, W., Grimm, P. C., Daldrup-Link, H. E. 2017

  Abstract

  To evaluate whether ultrasmall superparamagnetic iron oxide nanoparticle (USPIO)-enhanced magnetic resonance imaging (MRI) can detect allograft rejection in pediatric kidney transplant patients.The USPIO ferumoxytol has a long blood half-life and is phagocytosed by macrophages. In an IRB-approved single-center prospective clinical trial, 26 pediatric patients and adolescents (age 10-26 years) with acute allograft rejection (n = 5), non-rejecting allografts (n = 13), and normal native kidneys (n = 8) underwent multi-echo T2* fast spoiled gradient-echo (FSPGR) MRI after intravenous injection (p.i.) of 5 mg Fe/kg ferumoxytol. T2* relaxation times at 4 h p.i. (perfusion phase) and more than 20 h p.i. (macrophage phase) were compared with biopsy results. The presence of rejection was assessed using the Banff criteria, and the prevalence of macrophages on CD163 immunostains was determined based on a semi-quantitative scoring system. MRI and histology data were compared among patient groups using t tests, analysis of variance, and regression analyses with a significance threshold of p < 0.05.At 4 h p.i., mean T2* values were 6.6 ± 1.5 ms for native kidneys and 3.9 ms for one allograft undergoing acute immune rejection. Surprisingly, at 20-24 h p.i., one rejecting allograft showed significantly prolonged T2* relaxation times (37.0 ms) compared to native kidneys (6.3 ± 1.7 ms) and non-rejecting allografts (7.6 ± 0.1 ms). Likewise, three additional rejecting allografts showed significantly prolonged T2* relaxation times compared to non-rejecting allografts at later post-contrast time points, 25-97 h p.i. (p = 0.008). Histological analysis revealed edema and compressed microvessels in biopsies of rejecting allografts. Allografts with and without rejection showed insignificant differences in macrophage content on histopathology (p = 0.44).After ferumoxytol administration, renal allografts undergoing acute rejection show prolonged T2* values compared to non-rejecting allografts. Since histology revealed no significant differences in macrophage content, the increasing T2* value is likely due to the combined effect of reduced perfusion and increased edema in rejecting allografts.

  View details for DOI 10.1007/s11307-017-1084-8

  View details for PubMedID 28411307

• Current and potential imaging applications of ferumoxytol for magnetic resonance imaging. Kidney international Toth, G. B., Varallyay, C. G., Horvath, A., Bashir, M. R., Choyke, P. L., Daldrup-Link, H. E., Dosa, E., Finn, J. P., Gahramanov, S., Harisinghani, M., Macdougall, I., Neuwelt, A., Vasanawala, S. S., Ambady, P., Barajas, R., Cetas, J. S., Ciporen, J., DeLoughery, T. J., Doolittle, N. D., Fu, R., Grinstead, J., Guimaraes, A. R., Hamilton, B. E., Li, X., McConnell, H. L., Muldoon, L. L., Nesbit, G., Netto, J. P., Petterson, D., Rooney, W. D., Schwartz, D., Szidonya, L., Neuwelt, E. A. 2017

  Abstract

  Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phase and delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.

  View details for DOI 10.1016/j.kint.2016.12.037

  View details for PubMedID 28434822

• Detection of Stem Cell Transplant Rejection with Ferumoxytol MR Imaging: Correlation of MR Imaging Findings with Those at Intravital Microscopy. Radiology Daldrup-Link, H. E., Chan, C., Lenkov, O., Taghavigarmestani, S., Nazekati, T., Nejadnik, H., Chapelin, F., Khurana, A., Tong, X., Yang, F., Pisani, L., Longaker, M., Gambhir, S. S. 2017: 161139-?

  Abstract

  Purpose To determine whether endogenous labeling of macrophages with clinically applicable nanoparticles enables noninvasive detection of innate immune responses to stem cell transplants with magnetic resonance (MR) imaging. Materials and Methods Work with human stem cells was approved by the institutional review board and the stem cell research oversight committee, and animal experiments were approved by the administrative panel on laboratory animal care. Nine immunocompetent Sprague-Dawley rats received intravenous injection of ferumoxytol, and 18 Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice received rhodamine-conjugated ferumoxytol. Then, 48 hours later, immune-matched or mismatched stem cells were implanted into osteochondral defects of the knee joints of experimental rats and calvarial defects of Jax mice. All animals underwent serial MR imaging and intravital microscopy (IVM) up to 4 weeks after surgery. Macrophages of Jax C57BL/6-Tg (Csf1r-EGFP-NGFR/FKBP1A/TNFRSF6) 2Bck/J mice express enhanced green fluorescent protein (GFP), which enables in vivo correlation of ferumoxytol enhancement at MR imaging with macrophage quantities at IVM. All quantitative data were compared between experimental groups by using a mixed linear model and t tests. Results Immune-mismatched stem cell implants demonstrated stronger ferumoxytol enhancement than did matched stem cell implants. At 4 weeks, T2 values of mismatched implants were significantly lower than those of matched implants in osteochondral defects of female rats (mean, 10.72 msec for human stem cells and 11.55 msec for male rat stem cells vs 15.45 msec for sex-matched rat stem cells; P = .02 and P = .04, respectively) and calvarial defects of recipient mice (mean, 21.7 msec vs 27.1 msec, respectively; P = .0444). This corresponded to increased recruitment of enhanced GFP- and rhodamine-ferumoxytol-positive macrophages into stem cell transplants, as visualized with IVM and histopathologic examination. Conclusion Endogenous labeling of macrophages with ferumoxytol enables noninvasive detection of innate immune responses to stem cell transplants with MR imaging. (©) RSNA, 2017 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2017161139

  View details for PubMedID 28128708

• Photoacoustic Imaging of Embryonic Stem Cell-Derived Cardiomyocytes in Living Hearts with Ultrasensitive Semiconducting Polymer Nanoparticles Advanced Functional Materials Qin, X., Chen, H., Yang, H., Wu, H., Zhao, X., Wang, H., Chour, T., Neofytou, E., Ding, D., Daldrup-Link, H., Heilshorn, S. C., Li, K., Wu, J. C. 2017

  View details for DOI 10.1002/adfm.201704939

• Ten Things You Might Not Know about Iron Oxide Nanoparticles. Radiology Daldrup-Link, H. E. 2017; 284 (3): 616–29

  Abstract

  Amid mounting concerns about nephrogenic sclerosis and gadolinium deposition in the brain, physicians and patients alike are starting to question the use of gadolinium chelates for clinical magnetic resonance (MR) imaging. The search for safer alternatives is currently underway. In North America, the iron supplement ferumoxytol has gained considerable interest as an MR contrast agent. In Europe, ferumoxtran-10 is entering phase III clinical trials. As these agents are starting to be used by a new generation of radiologists, important clinical questions have re-emerged, including those that have been answered in the past. This article offers 10 important insights for the use of iron oxide nanoparticles in clinical MR imaging.

  View details for PubMedID 28825888

• The Fermi Paradox in STEM-Where Are the Women Leaders? Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Daldrup-Link, H. E. 2017

  Abstract

  This commentary summarizes insights and discussions about the status of women leaders in STEM (science, technology, engineering, and medicine). While many academic institutions now train close to 50 % female students in STEM disciplines, there is a major underrepresentation of qualified women in leadership roles. Women are admitted to the basements of STEM institutions, but only few make it to the top floor. We see male superstars receiving well-deserved recognitions and advancements. Unfortunately, their female counterparts are often held back or cut down by both male and female colleagues. Increasing reports of acts of discrimination reported by women in STEM fields are a symptom. Unilateral hierarchy is the root cause. Just increasing the quote/proportion of women and underrepresented minorities at an institution is therefore not enough to address the underlying problem. At Stanford Radiology, we started a major initiative to increase the representation of qualified women and other underrepresented minorities in our leadership teams in order to ensure that every member of the Department has an advocate at the leadership table, when decisions are being made. Diverse leadership teams are vital to creating a culture of respect and inclusion for everyone.

  View details for PubMedID 28924727

• Whole-body PET/MRI of Pediatric Patients: The Details That Matter. Journal of visualized experiments : JoVE Pareek, A., Muehe, A. M., Theruvath, A. J., Gulaka, P. K., Spunt, S. L., Daldrup-Link, H. E. 2017

  Abstract

  Integrated PET/MRI is a hybrid imaging technique enabling clinicians to acquire diagnostic images for tumor assessment and treatment monitoring with both high soft tissue contrast and added metabolic information. Integrated PET/MRI has shown to be valuable in the clinical setting and has many promising future applications. The protocol presented here will provide step-by-step instructions for the acquisition of whole-body 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/MRI data in children with cancer. It also provides instructions on how to combine a whole-body staging scan with a local tumor scan for evaluation of the primary tumor. The focus of this protocol is to be both comprehensive and time-efficient, which are two ubiquitous needs for clinical applications. This protocol was originally developed for children above 6 years, or old enough to comply with breath-hold instructions, but can also be applied to patients under general anesthesia. Similarly, this protocol can be modified to fit institutional preferences in terms of choice of MRI pulse sequences for both the whole-body scan and local tumor assessment.

  View details for PubMedID 29286486

• The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging. Radiology Nejadnik, H., Taghavi-Garmestani, S. M., Madsen, S. J., Li, K., Zanganeh, S., Yang, P., Mahmoudi, M., Daldrup-Link, H. E. 2017: 170130

  Abstract

  Purpose To evaluate if the formation of a protein corona around ferumoxytol nanoparticles can facilitate stem cell labeling for in vivo tracking with magnetic resonance (MR) imaging. Materials and Methods Ferumoxytol was incubated in media containing human serum (group 1), fetal bovine serum (group 2), StemPro medium (group 3), protamine (group 4), and protamine plus heparin (group 5). Formation of a protein corona was characterized by means of dynamic light scattering, ζ potential, and liquid chromatography-mass spectrometry. Iron uptake was evaluated with 3,3'-diaminobenzidine-Prussian blue staining, lysosomal staining, and inductively coupled plasma spectrometry. To evaluate the effect of a protein corona on stem cell labeling, human mesenchymal stem cells (hMSCs) were labeled with the above formulations, implanted into pig knee specimens, and investigated with T2-weighted fast spin-echo and multiecho spin-echo sequences on a 3.0-T MR imaging unit. Data in different groups were compared by using a Kruskal-Wallis test. Results Compared with bare nanoparticles, all experimental groups showed significantly increased negative ζ values (from -37 to less than -10; P = .008). Nanoparticles in groups 1-3 showed an increased size because of the formation of a protein corona. hMSCs labeled with group 1-5 media showed significantly shortened T2 relaxation times compared with unlabeled control cells (P = .0012). hMSCs labeled with group 3 and 5 media had the highest iron uptake after cells labeled with group 1 medium. After implantation into pig knees, hMSCs labeled with group 1 medium showed significantly shorter T2 relaxation times than hMSCs labeled with group 2-5 media (P = .0022). Conclusion The protein corona around ferumoxytol nanoparticles can facilitate stem cell labeling for clinical cell tracking with MR imaging. (©) RSNA, 2017 Online supplemental material is available for this article.

  View details for PubMedID 29091749

• How PET/MR Can Add Value For Children With Cancer. Current radiology reports Daldrup-Link, H. 2017; 5 (3)

  Abstract

  To review how PET/MR technology could add value for pediatric cancer patients.Since many primary tumors in children are evaluated with MRI and metastases are detected with PET/CT, integrated PET/MR can be a time-efficient and convenient solution for pediatric cancer staging. (18)F-FDG PET/MR can assess primary tumors and the whole body in one imaging session, avoid repetitive anesthesia and reduce radiation exposure compared to (18)F-FDG PET/CT. This article lists 10 action points, which might improve the clinical value of PET/MR for children with cancer. However, even if PET/MR proves valuable, it cannot enter mainstream applications if it is not accessible to the majority of pediatric cancer patients. Therefore, innovations are needed to make PET/MR scanners affordable and increase patient throughput.PET/MR offers opportunities for more efficient, accurate and safe diagnoses of pediatric cancer patients. The impact on patient management and outcomes has to be substantiated by large-scale prospective clinical trials.

  View details for PubMedID 28695063

  View details for PubMedCentralID PMC5501255

• Bone marrow oedema predicts bone collapse in paediatric and adolescent leukaemia patients with corticosteroid-induced osteonecrosis. European radiology Theruvath, A. J., Sukerkar, P. A., Bao, S., Rosenberg, J., Luna-Fineman, S., Kharbanda, S., Daldrup-Link, H. E. 2017

  Abstract

  Corticosteroid treatment of paediatric leukaemia patients can lead to osteonecrosis (ON). We determined whether bone marrow oedema (BME) is an early sign of progressive ON and eventual bone collapse.In a retrospective study, two radiologists reviewed MR imaging characteristics of 47 early stage epiphyseal ON in 15 paediatric and adolescent leukaemia patients. Associations between BME on initial imaging studies and subchondral fracture, disease progression and bone collapse were assessed by Cochran-Mantel-Haenszel tests. Differences in time to progression and bone collapse between lesions with and without oedema were assessed by log rank tests.Forty-seven occurrences of ON were located in weight bearing joints, with 77% occurring in the femur. Seventeen lesions progressed to collapse, two lesions worsened without collapse, and 28 remained stable or improved. BME was significantly associated with subchondral fracture (p = 0.0014), disease progression (p = 0.0015), and bone collapse (p < 0.001), with a sensitivity and specificity of 94% and 77%, respectively, for bone collapse. Time to progression for ON with oedema was 2.7 years (95% CI: 1.7-3.4); while the majority of no-oedema ON were stable (p = 0.0011).BME is an early sign of progressive ON and eventual bone collapse in paediatric and adolescent leukaemia patients.• Bone marrow oedema in corticosteroid-induced osteonecrosis predicts progression to bone collapse. • Bone marrow oedema is associated with subchondral fractures in corticosteroid-induced osteonecrosis. • Bone marrow oedema can be used to stratify patients to joint-preserving interventions. • Absence of bone marrow oedema can justify a "wait and watch" approach.

  View details for PubMedID 28726121

• Assessment of Chemotherapy Response in Ewing Sarcoma Response RADIOLOGY Daldrup-Link, H. E., DuBois, S. G., Aghighi, M., Marina, N., Petit, P. 2016; 281 (2): 648–49

  View details for Web of Science ID 000393199200041

• Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. The Lancet. Oncology Marina, N. M., Smeland, S., Bielack, S. S., Bernstein, M., Jovic, G., Krailo, M. D., Hook, J. M., Arndt, C., van den Berg, H., Brennan, B., Brichard, B., Brown, K. L., Butterfass-Bahloul, T., Calaminus, G., Daldrup-Link, H. E., Eriksson, M., Gebhardt, M. C., Gelderblom, H., Gerss, J., Goldsby, R., Goorin, A., Gorlick, R., Grier, H. E., Hale, J. P., Hall, K. S., Hardes, J., Hawkins, D. S., Helmke, K., Hogendoorn, P. C., Isakoff, M. S., Janeway, K. A., Jürgens, H., Kager, L., Kühne, T., Lau, C. C., Leavey, P. J., Lessnick, S. L., Mascarenhas, L., Meyers, P. A., Mottl, H., Nathrath, M., Papai, Z., Randall, R. L., Reichardt, P., Renard, M., Safwat, A. A., Schwartz, C. L., Stevens, M. C., Strauss, S. J., Teot, L., Werner, M., Sydes, M. R., Whelan, J. S. 2016; 17 (10): 1396-1408

  Abstract

  We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m(2), doxorubicin 37·5 mg/m(2) per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m(2) over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m(2)) at 2·8 g/m(2) per day with equidose mesna uroprotection, followed by etoposide 100 mg/m(2) per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting.UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

  View details for DOI 10.1016/S1470-2045(16)30214-5

  View details for PubMedID 27569442

• Three-dimensional Radiologic Assessment of Chemotherapy Response in Ewing Sarcoma Can Be Used to Predict Clinical Outcome. Radiology Aghighi, M., Boe, J., Rosenberg, J., von Eyben, R., Gawande, R. S., Petit, P., Sethi, T. K., Sharib, J., Marina, N. M., DuBois, S. G., Daldrup-Link, H. E. 2016; 280 (3): 905-915

  Abstract

  Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age ± standard deviation, 14.5 years ± 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted κ statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016151301

  View details for PubMedID 26982677

• Macrophage phagocytosis alters the MRI signal of ferumoxytol-labeled mesenchymal stromal cells in cartilage defects SCIENTIFIC REPORTS Nejadnik, H., Lenkov, O., Gassert, F., Fretwell, D., Lam, I., Daldrup-Link, H. E. 2016; 6

  Abstract

  Human mesenchymal stem cells (hMSCs) are a promising tool for cartilage regeneration in arthritic joints. hMSC labeling with iron oxide nanoparticles enables non-invasive in vivo monitoring of transplanted cells in cartilage defects with MR imaging. Since graft failure leads to macrophage phagocytosis of apoptotic cells, we evaluated in vitro and in vivo whether nanoparticle-labeled hMSCs show distinct MR signal characteristics before and after phagocytosis by macrophages. We found that apoptotic nanoparticle-labeled hMSCs were phagocytosed by macrophages while viable nanoparticle-labeled hMSCs were not. Serial MRI scans of hMSC transplants in arthritic joints of recipient rats showed that the iron signal of apoptotic, nanoparticle-labeled hMSCs engulfed by macrophages disappeared faster compared to viable hMSCs. This corresponded to poor cartilage repair outcomes of the apoptotic hMSC transplants. Therefore, rapid decline of iron MRI signal at the transplant site can indicate cell death and predict incomplete defect repair weeks later. Currently, hMSC graft failure can be only diagnosed by lack of cartilage defect repair several months after cell transplantation. The described imaging signs can diagnose hMSC transplant failure more readily, which could enable timely re-interventions and avoid unnecessary follow up studies of lost transplants.

  View details for DOI 10.1038/srep25897

  View details for Web of Science ID 000375769300001

  View details for PubMedID 27174199

• Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors. JCI insight Daldrup-Link, H. E., Mohanty, S., Ansari, C., Lenkov, O., Shaw, A., Ito, K., Hong, S. H., Hoffmann, M., Pisani, L., Boudreau, N., Gambhir, S. S., Coussens, L. M. 2016; 1 (6)

  Abstract

  Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies.

  View details for PubMedID 27182558

• White Paper on P4 Concepts for Pediatric Imaging JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Daldrup-Link, H. E., Sammet, C., Hernanz-Schulman, M., Barsness, K. A., Cahill, A. M., Chung, E., Doria, A. S., Darge, K., Krishnamurthy, R., Lungren, M. P., Moore, S., Olivieri, L., Panigrahy, A., Towbin, A. J., Trout, A., Voss, S. 2016; 13 (5): 590-597

  Abstract

  Over the past decade, innovations in the field of pediatric imaging have been based largely on single-center and retrospective studies, which provided limited advances for the benefit of pediatric patients. To identify opportunities for potential "quantum-leap" progress in the field of pediatric imaging, the ACR-Pediatric Imaging Research (PIR) Committee has identified high-impact research directions related to the P4 concept of predictive, preventive, personalized, and participatory diagnosis and intervention. Input from 237 members of the Society for Pediatric Radiology was clustered around 10 priority areas, which are discussed in this article. Needs within each priority area have been analyzed in detail by ACR-PIR experts on these topics. By facilitating work in these priority areas, we hope to revolutionize the care of children by shifting our efforts from unilateral reaction to clinical symptoms, to interactive maintenance of child health.

  View details for DOI 10.1016/j.jacr.2015.10.028

  View details for PubMedID 26850380

• Speeding up PET/MR for cancer staging of children and young adults. European radiology Aghighi, M., Pisani, L. J., Sun, Z., Klenk, C., Madnawat, H., Fineman, S. L., Advani, R., von Eyben, R., Owen, D., Quon, A., Moseley, M., Daldrup-Link, H. E. 2016: -?

  Abstract

  Combining (18)F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared (18)F-FDG PET/STIR with accelerated (18)F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults.Thirty-three children and young adults (17.5 ± 5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a (18)F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. (18)F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively.Comparing (18)F-FDG PET/FSPGR to (18)F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001).F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to (18)F-FDG PET/STIR, but could be acquired with shorter acquisition time.• Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • (18) F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to (18) F-FDG PET/STIR.

  View details for PubMedID 27048532

• Safety Report of Ferumoxytol for Magnetic Resonance Imaging in Children and Young Adults INVESTIGATIVE RADIOLOGY Muehe, A. M., Feng, D., von Eyben, R., Luna-Fineman, S., Link, M. P., Muthig, T., Huddleston, A. E., Neuwelt, E. A., Daldrup-Link, H. E. 2016; 51 (4): 221-227

  Abstract

  The aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children.We prospectively evaluated the safety of ferumoxytol administrations as an "off-label" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model.Four mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection.Ferumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions.

  View details for DOI 10.1097/RLI.0000000000000230

  View details for Web of Science ID 000372451200002

  View details for PubMedCentralID PMC4783197

• Progressing Toward a Cohesive Pediatric 18F-FDG PET/MR Protocol: Is Administration of Gadolinium Chelates Necessary? Journal of nuclear medicine : official publication, Society of Nuclear Medicine Klenk, C., Gawande, R., Tran, V. T., Leung, J. T., Chi, K., Owen, D., Luna-Fineman, S., Sakamoto, K. M., McMillan, A., Quon, A., Daldrup-Link, H. E. 2016; 57 (1): 70-77

  Abstract

  With the increasing availability of integrated PET/MR scanners, the utility and need for MR contrast agents for combined scans is questioned. The purpose of our study was to evaluate whether administration of gadolinium chelates is necessary for evaluation of pediatric tumors on (18)F-FDG PET/MR images.First, in 119 pediatric patients with primary and secondary tumors, we used 14 diagnostic criteria to compare the accuracy of several MR sequences: unenhanced T2-weighted fast spin-echo imaging; unenhanced diffusion-weighted imaging; and-before and after gadolinium chelate contrast enhancement-T1-weighted 3-dimensional spoiled gradient echo LAVA (liver acquisition with volume acquisition) imaging. Next, in a subset of 36 patients who had undergone (18)F-FDG PET within 3 wk of MRI, we fused the PET images with the unenhanced T2-weighted MR images (unenhanced (18)F-FDG PET/MRI) and the enhanced T1-weighted MR images (enhanced (18)F-FDG PET/MRI). Using the McNemar test, we compared the accuracy of the two types of fused images using the 14 diagnostic criteria. We also evaluated the concordance between (18)F-FDG avidity and gadolinium chelate enhancement. The standard of reference was histopathologic results, surgical notes, and follow-up imaging.There was no significant difference in diagnostic accuracy between the unenhanced and enhanced MR images. Accordingly, there was no significant difference in diagnostic accuracy between the unenhanced and enhanced (18)F-FDG PET/MR images. (18)F-FDG avidity and gadolinium chelate enhancement were concordant in 30 of the 36 patients and 106 of their 123 tumors.Gadolinium chelate administration is not necessary for accurate diagnostic characterization of most solid pediatric malignancies on (18)F-FDG PET/MR images, with the possible exception of focal liver lesions.

  View details for DOI 10.2967/jnumed.115.161646

  View details for PubMedID 26471690

• Safety Report of Ferumoxytol for Magnetic Resonance Imaging in Children and Young Adults. Investigative radiology Muehe, A. M., Feng, D., von Eyben, R., Luna-Fineman, S., Link, M. P., Muthig, T., Huddleston, A. E., Neuwelt, E. A., Daldrup-Link, H. E. 2016; 51 (4): 221–27

  Abstract

  The aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children.We prospectively evaluated the safety of ferumoxytol administrations as an "off-label" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model.Four mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection.Ferumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions.

  View details for PubMedID 26656202

• Progressing Toward a Cohesive Pediatric F-18-FDG PET/MR Protocol: Is Administration of Gadolinium Chelates Necessary? JOURNAL OF NUCLEAR MEDICINE Klenk, C., Gawande, R., Vy Thao Tran, V. T., Leung, J. T., Chi, K., Owen, D., Luna-Fineman, S., Sakamoto, K. M., McMillan, A., Quon, A., Daldrup-Link, H. E. 2016; 57 (1): 70-77

  Abstract

  With the increasing availability of integrated PET/MR scanners, the utility and need for MR contrast agents for combined scans is questioned. The purpose of our study was to evaluate whether administration of gadolinium chelates is necessary for evaluation of pediatric tumors on (18)F-FDG PET/MR images.First, in 119 pediatric patients with primary and secondary tumors, we used 14 diagnostic criteria to compare the accuracy of several MR sequences: unenhanced T2-weighted fast spin-echo imaging; unenhanced diffusion-weighted imaging; and-before and after gadolinium chelate contrast enhancement-T1-weighted 3-dimensional spoiled gradient echo LAVA (liver acquisition with volume acquisition) imaging. Next, in a subset of 36 patients who had undergone (18)F-FDG PET within 3 wk of MRI, we fused the PET images with the unenhanced T2-weighted MR images (unenhanced (18)F-FDG PET/MRI) and the enhanced T1-weighted MR images (enhanced (18)F-FDG PET/MRI). Using the McNemar test, we compared the accuracy of the two types of fused images using the 14 diagnostic criteria. We also evaluated the concordance between (18)F-FDG avidity and gadolinium chelate enhancement. The standard of reference was histopathologic results, surgical notes, and follow-up imaging.There was no significant difference in diagnostic accuracy between the unenhanced and enhanced MR images. Accordingly, there was no significant difference in diagnostic accuracy between the unenhanced and enhanced (18)F-FDG PET/MR images. (18)F-FDG avidity and gadolinium chelate enhancement were concordant in 30 of the 36 patients and 106 of their 123 tumors.Gadolinium chelate administration is not necessary for accurate diagnostic characterization of most solid pediatric malignancies on (18)F-FDG PET/MR images, with the possible exception of focal liver lesions.

  View details for DOI 10.2967/jnumed.115.161646

  View details for Web of Science ID 000367862700014

  View details for PubMedCentralID PMC4703553

• Improved Approach for Chondrogenic Differentiation of Human Induced Pluripotent Stem Cells STEM CELL REVIEWS AND REPORTS Nejadnik, H., Diecke, S., Lenkov, O. D., Chapelin, F., Donig, J., Tong, X., Derugin, N., Chan, R. C., Gaur, A., Yang, F., Wu, J. C., Daldrup-Link, H. E. 2015; 11 (2): 242-253

  Abstract

  Human induced pluripotent stem cells (hiPSCs) have demonstrated great potential for hyaline cartilage regeneration. However, current approaches for chondrogenic differentiation of hiPSCs are complicated and inefficient primarily due to intermediate embryoid body formation, which is required to generate endodermal, ectodermal, and mesodermal cell lineages. We report a new, straightforward and highly efficient approach for chondrogenic differentiation of hiPSCs, which avoids embryoid body formation. We differentiated hiPSCs directly into mesenchymal stem /stromal cells (MSC) and chondrocytes. hiPSC-MSC-derived chondrocytes showed significantly increased Col2A1, GAG, and SOX9 gene expression compared to hiPSC-MSCs. Following transplantation of hiPSC-MSC and hiPSC-MSC-derived chondrocytes into osteochondral defects of arthritic joints of athymic rats, magnetic resonance imaging studies showed gradual engraftment, and histological correlations demonstrated hyaline cartilage matrix production. Results present an efficient and clinically translatable approach for cartilage tissue regeneration via patient-derived hiPSCs, which could improve cartilage regeneration outcomes in arthritic joints.

  View details for DOI 10.1007/s12015-014-9581-5

  View details for Web of Science ID 000353149700004

  View details for PubMedID 25578634

• Current methods for reducing intussusception: survey results PEDIATRIC RADIOLOGY Stein-Wexler, R., O'Connor, R., Daldrup-Link, H., Wootton-Gorges, S. L. 2015; 45 (5): 667-674

  Abstract

  Intussusception is a common pediatric abdominal emergency, treated with image-guided reduction. Available techniques include fluoroscopic and ultrasonographic monitoring of liquid and air.The purpose of this study was to determine current practices and establish trends by comparing our findings with reports of previous surveys.This study is based on an e-mail survey sent to all 1,538 members of the Society for Pediatric Radiology. It included questions about demographics, presence of parents/surgeon during procedure, patient selection/preparation, use of sedation, preferred methods of reduction and technical details, approach to unsuccessful reduction, and self-reported incidence of success/perforation.The 456 respondents (30%) reported attempting 3,834 reductions in the preceding 12 months. Of these, 96% use fluoroscopy and 4% use US guidance for reduction; 78% use air, 20% prefer fluid; 75% require intravenous access; 63% expect a surgeon to be present in hospital; 93% do not sedate. Although inflating a rectal balloon is controversial, 39% do so, and 50% employ a pressure-release valve. Seventy-two percent attempt reductions three times in the same position. In case of unsuccessful reductions, 64% wait and re-attempt later, 19% apply manual pressure, and 15% try again in left decubitus position. About 20% reattempt reduction after waiting 2 h or more.By providing a better understanding of both trends in and diversity of current practice, we hope to increase the confidence with which the individual practitioner will approach each case.

  View details for DOI 10.1007/s00247-014-3214-7

  View details for Web of Science ID 000353234800008

  View details for PubMedID 25432441

• Magnetic resonance imaging of stem cell apoptosis in arthritic joints with a caspase activatable contrast agent. ACS nano Nejadnik, H., Ye, D., Lenkov, O. D., Donig, J. S., Martin, J. E., Castillo, R., Derugin, N., Sennino, B., Rao, J., Daldrup-Link, H. 2015; 9 (2): 1150-1160

  Abstract

  About 43 million individuals in the U.S. encounter cartilage injuries due to trauma or osteoarthritis, leading to joint pain and functional disability. Matrix-associated stem cell implants (MASI) represent a promising approach for repair of cartilage defects. However, limited survival of MASI creates a significant bottleneck for successful cartilage regeneration outcomes and functional reconstitution. We report an approach for noninvasive detection of stem cell apoptosis with magnetic resonance imaging (MRI), based on a caspase-3-sensitive nanoaggregation MRI probe (C-SNAM). C-SNAM self-assembles into nanoparticles after hydrolysis by caspase-3, leading to 90% amplification of (1)H MR signal and prolonged in vivo retention. Following intra-articular injection, C-SNAM causes significant MR signal enhancement in apoptotic MASI compared to viable MASI. Our results indicate that C-SNAM functions as an imaging probe for stem cell apoptosis in MASI. This concept could be applied to a broad range of cell transplants and target sites.

  View details for DOI 10.1021/nn504494c

  View details for PubMedID 25597243

• Value of F-18-FDG PET and PET/CT for Evaluation of Pediatric Malignancies JOURNAL OF NUCLEAR MEDICINE Uslu, L., Donig, J., Link, M., Rosenberg, J., Quon, A., Daldrup-Link, H. E. 2015; 56 (2): 274-286

  Abstract

  Successful management of solid tumors in children requires imaging tests for accurate disease detection, characterization, and treatment monitoring. Technologic developments aim toward the creation of integrated imaging approaches that provide a comprehensive diagnosis with a single visit. These integrated diagnostic tests not only are convenient for young patients but also save direct and indirect health-care costs by streamlining procedures, minimizing hospitalizations, and minimizing lost school or work time for children and their parents. (18)F-FDG PET/CT is a highly sensitive and specific imaging modality for whole-body evaluation of pediatric malignancies. However, recent concerns about ionizing radiation exposure have led to a search for alternative imaging methods, such as whole-body MR imaging and PET/MR. As we develop new approaches for tumor staging, it is important to understand current benchmarks. This review article will synthesize the current literature on (18)F-FDG PET/CT for tumor staging in children, summarizing questions that have been solved and providing an outlook on unsolved avenues.

  View details for DOI 10.2967/jnumed.114.146290

  View details for Web of Science ID 000349324300030

• Value of 18F-FDG PET and PET/CT for evaluation of pediatric malignancies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Uslu, L., Donig, J., Link, M., Rosenberg, J., Quon, A., Daldrup-Link, H. E. 2015; 56 (2): 274-286

  Abstract

  Successful management of solid tumors in children requires imaging tests for accurate disease detection, characterization, and treatment monitoring. Technologic developments aim toward the creation of integrated imaging approaches that provide a comprehensive diagnosis with a single visit. These integrated diagnostic tests not only are convenient for young patients but also save direct and indirect health-care costs by streamlining procedures, minimizing hospitalizations, and minimizing lost school or work time for children and their parents. (18)F-FDG PET/CT is a highly sensitive and specific imaging modality for whole-body evaluation of pediatric malignancies. However, recent concerns about ionizing radiation exposure have led to a search for alternative imaging methods, such as whole-body MR imaging and PET/MR. As we develop new approaches for tumor staging, it is important to understand current benchmarks. This review article will synthesize the current literature on (18)F-FDG PET/CT for tumor staging in children, summarizing questions that have been solved and providing an outlook on unsolved avenues.

  View details for DOI 10.2967/jnumed.114.146290

  View details for PubMedID 25572088

• Imaging Tumor Necrosis with Ferumoxytol. PloS one Aghighi, M., Golovko, D., Ansari, C., Marina, N. M., Pisani, L., Kurlander, L., Klenk, C., Bhaumik, S., Wendland, M., Daldrup-Link, H. E. 2015; 10 (11)

  View details for DOI 10.1371/journal.pone.0142665

  View details for PubMedID 26569397

• Imaging Tumor Necrosis with Ferumoxytol. PloS one Aghighi, M., Golovko, D., Ansari, C., Marina, N. M., Pisani, L., Kurlander, L., Klenk, C., Bhaumik, S., Wendland, M., Daldrup-Link, H. E. 2015; 10 (11)

  Abstract

  Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated proton relaxation rate enhancement is strongly dependent on compartmentalization of the agent and can vary depending on their intracellular or extracellular location in the tumor microenvironment. We compared the T1- and T2-enhancement pattern of intracellular and extracellular USPIO in mouse models of cancer and pilot data from patients. A better understanding of these MR signal effects will enable non-invasive characterizations of the composition of the tumor microenvironment.Six 4T1 and six MMTV-PyMT mammary tumors were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates were calculated for different tumor types and different tumor areas and compared with histology. The transendothelial leakage rate of ferumoxytol was obtained by our measured relaxivity of ferumoxytol and compared between different tumor types, using a t-test. Additionally, 3 patients with malignant sarcomas were imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were compared with histopathology in a descriptive manner as a proof of concept for clinical translation of our observations.4T1 tumors showed central areas of high signal on T1 and low signal on T2 weighted MR images, which corresponded to extracellular nanoparticles in a necrotic core on histopathology. MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted images, which correlated to compartmentalized nanoparticles in tumor associated macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation rates of the tumor core compared to the tumor periphery (p<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients showed similar findings with high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron.Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment.

  View details for DOI 10.1371/journal.pone.0142665

  View details for PubMedID 26569397

• Clinical applications of iron oxide nanoparticles for magnetic resonance imaging of brain tumors NANOMEDICINE Iv, M., Telischak, N., Feng, D., Holdsworth, S. J., Yeom, K. W., Daldrup-Link, H. E. 2015; 10 (6): 993-1018

  Abstract

  Current neuroimaging provides detailed anatomic and functional evaluation of brain tumors, allowing for improved diagnostic and prognostic capabilities. Some challenges persist even with today's advanced imaging techniques, including accurate delineation of tumor margins and distinguishing treatment effects from residual or recurrent tumor. Ultrasmall superparamagnetic iron oxide nanoparticles are an emerging tool that can add clinically useful information due to their distinct physiochemical features and biodistribution, while having a good safety profile. Nanoparticles can be used as a platform for theranostic drugs, which have shown great promise for the treatment of CNS malignancies. This review will provide an overview of clinical ultrasmall superparamagnetic iron oxides and how they can be applied to the diagnostic and therapeutic neuro-oncologic setting.

  View details for DOI 10.2217/NNM.14.203

  View details for Web of Science ID 000352806000009

  View details for PubMedID 25867862

• ACR Committee on Pediatric Imaging Research. Pediatric radiology Daldrup-Link, H. E., Voss, S., Donig, J. 2014; 44 (9): 1193-1194

  View details for DOI 10.1007/s00247-013-2850-7

  View details for PubMedID 25142332

• Basic science research in pediatric radiology - how to empower the leading edge of our field PEDIATRIC RADIOLOGY Daldrup-Link, H. E. 2014; 44 (8): 935–39

  Abstract

  Basic science research aims to explore, understand and predict phenomena in the natural world. It spurs the discovery of fundamentally new principles and leads to new knowledge and new concepts. By comparison, applied research employs basic science knowledge toward practical applications. In the clinical realm, basic science research and applied research should be closely connected. Basic science discoveries can build the foundation for a broad range of practical applications and thereby bring major benefits to human health, education, environment and economy. This article explains how basic science research impacts our field, it describes examples of new research directions in pediatric imaging and it outlines current challenges that we need to overcome in order to enable the next groundbreaking discovery.

  View details for DOI 10.1007/s00247-014-2958-4

  View details for Web of Science ID 000339903000005

  View details for PubMedID 25060618

• Successful Treatment with Temozolomide Combined with Chemoradiotherapy and Surgery of a Metastatic Undifferentiated Soft Tissue Sarcoma with Relapse in the Central Nervous System of a Young Adult JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY Hsu, C. H., Daldrup-Link, H. E., Yeom, K. W., Donaldson, S. S., Million, L., Hazard, F. K., Rangaswami, A. 2014; 3 (2): 100-103

  View details for DOI 10.1089/jayao.2013.0041

  View details for Web of Science ID 000350130800008

• (18)F-FDG PET/CT scans for children and adolescents - authors' reply. lancet oncology Daldrup-Link, H., Quon, A., Goske, M. 2014; 15 (7)

  View details for DOI 10.1016/S1470-2045(14)70222-0

  View details for PubMedID 24872100

• Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 566-?

  Abstract

  A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional "theranostic" nanoparticles (TNPs) is described for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death is observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.

  View details for DOI 10.1002/smll.201301456

  View details for PubMedID 24038954

• MR Imaging of Stem Cell Transplants in Arthritic Joints. Journal of stem cell research & therapy Daldrup-Link, H. E., Nejadnik, H. 2014; 4 (2): 165-?

  Abstract

  About 43 million individuals in the US currently suffer from disabilities due to arthritis. Cartilage defects are the major source of pain in the affected joints. Current treatments, whilst alleviating some of the clinical symptoms, prove insufficient to cure the underlying irreversible cartilage loss. Stem cells represent a unique source for restoration of cartilage defects. Pre-clinical and clinical trials are currently pursued to investigate the potential of various types of stem cells and stem cell derived chondrocytes to repair arthritic joints. A major challenge with all stem cell-mediated tissue regeneration approaches is death of the transplanted cells with clearance by the immune system. Our current inability to diagnose successful or unsuccessful engraftment of transplanted cells non-invasively in vivo represents a major bottleneck for the development of successful stem cell therapies. A large variety of non-invasive Magnetic Resonance (MR) imaging techniques have been developed over the last decade, which enable sensitive in vivo detection of Matrix Associated Stem Cell Implants (MASI) and early diagnosis of related complications. While initially focused on successfully harvesting cellular MR imaging approaches with easily applicable SuperParamagnetic Iron Oxide Nanoparticles (SPIO), our team began to observe details that will facilitate clinical translation. We therefore started a broader effort to define a comprehensive set of novel, clinically applicable imaging approaches for stem cell transplants in patients. We established immediately clinically applicable nanoparticle labeling techniques for tracking stem cell transplants with MR imaging; we have evaluated the long term MR signal effects of iron oxide nanoparticle labeled MASI in vivo; and we have defined distinct signal characteristics of labeled viable and apoptotic MASI. This review article will provide an overview over these efforts and discuss important implications for clinical translation.

  View details for PubMedID 25068075

  View details for PubMedCentralID PMC4110919

• Comparison of Latino and Non-Latino Patients With Ewing Sarcoma PEDIATRIC BLOOD & CANCER Sharib, J., Horvai, A., Hazard, F. K., Daldrup-Link, H., Goldsby, R., Marina, N., DuBois, S. G. 2014; 61 (2): 233-237

  Abstract

  Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES.Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing.Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54).Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.

  View details for DOI 10.1002/pbc.24745

  View details for Web of Science ID 000328694300016

  View details for PubMedID 23970433

• Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 566-575

  View details for DOI 10.1002/smll.201301456

  View details for PubMedID 24038954

• Cancer therapy: development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy (small 3/2014). Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 417-?

  Abstract

  Cancer cells overexpress matrix-type metalloproteinases (MMPs, shown as pacmen). MMPs cleave the peptide linker connecting anticancer prodrug to the dextran coated magnetic nanoparticle. After the cleavage, the drug becomes toxic (active drug shown in purple). As J. Rao, H. E. Daldrup-Link, and co-workers describe on page 566, this tumor specific drug release reduces the side-effects of cancer therapy. The magnetic core of the nanoparticles allows for MRI monitoring of their distribution in the body.

  View details for DOI 10.1002/smll.201470016

  View details for PubMedID 24497471

• Ferumoxytol: a new, clinically applicable label for stem-cell tracking in arthritic joints with MRI. Nanomedicine Khurana, A., Nejadnik, H., Chapelin, F., Lenkov, O., Gawande, R., Lee, S., Gupta, S. N., Aflakian, N., Derugin, N., Messing, S., Lin, G., Lue, T. F., Pisani, L., Daldrup-Link, H. E. 2013; 8 (12): 1969-1983

  Abstract

  Aim: To develop a clinically applicable MRI technique for tracking stem cells in matrix-associated stem-cell implants, using the US FDA-approved iron supplement ferumoxytol. Materials & methods: Ferumoxytol-labeling of adipose-derived stem cells (ADSCs) was optimized in vitro. A total of 11 rats with osteochondral defects of both femurs were implanted with ferumoxytol- or ferumoxides-labeled or unlabeled ADSCs, and underwent MRI up to 4 weeks post matrix-associated stem-cell implant. The signal-to-noise ratio of different matrix-associated stem-cell implant was compared with t-tests and correlated with histopathology. Results: An incubation concentration of 500 µg iron/ml ferumoxytol and 10 µg/ml protamine sulfate led to significant cellular iron uptake, T2 signal effects and unimpaired ADSC viability. In vivo, ferumoxytol- and ferumoxides-labeled ADSCs demonstrated significantly lower signal-to-noise ratio values compared with unlabeled controls (p < 0.01). Histopathology confirmed engraftment of labeled ADSCs, with slow dilution of the iron label over time. Conclusion: Ferumoxytol can be used for in vivo tracking of stem cells with MRI. Original submitted 28 February 2012; Revised submitted 8 November 2012.

  View details for DOI 10.2217/nnm.12.198

  View details for PubMedID 23534832

• Iron Administration before Stem Cell Harvest Enables MR Imaging Tracking after Transplantation. Radiology Khurana, A., Chapelin, F., Beck, G., Lenkov, O. D., Donig, J., Nejadnik, H., Messing, S., Derugin, N., Chan, R. C., Gaur, A., Sennino, B., McDonald, D. M., Kempen, P. J., Tikhomirov, G. A., Rao, J., Daldrup-Link, H. E. 2013; 269 (1): 186-197

  Abstract

  Purpose:To determine whether intravenous ferumoxytol can be used to effectively label mesenchymal stem cells (MSCs) in vivo and can be used for tracking of stem cell transplants.Materials and Methods:This study was approved by the institutional animal care and use committee. Sprague-Dawley rats (6-8 weeks old) were injected with ferumoxytol 48 hours prior to extraction of MSCs from bone marrow. Ferumoxytol uptake by these MSCs was evaluated with fluorescence, confocal, and electron microscopy and compared with results of traditional ex vivo-labeling procedures. The in vivo-labeled cells were subsequently transplanted in osteochondral defects of 14 knees of seven athymic rats and were evaluated with magnetic resonance (MR) imaging up to 4 weeks after transplantation. T2 relaxation times of in vivo-labeled MSC transplants and unlabeled control transplants were compared by using t tests. MR data were correlated with histopathologic results.Results:In vivo-labeled MSCs demonstrated significantly higher ferumoxytol uptake compared with ex vivo-labeled cells. With electron microscopy, iron oxide nanoparticles were localized in secondary lysosomes. In vivo-labeled cells demonstrated significant T2 shortening effects in vitro and in vivo when they were compared with unlabeled control cells (T2 in vivo, 15.4 vs 24.4 msec; P < .05) and could be tracked in osteochondral defects for 4 weeks. Histologic examination confirmed the presence of iron in labeled transplants and defect remodeling.Conclusion:Intravenous ferumoxytol can be used to effectively label MSCs in vivo and can be used for tracking of stem cell transplants with MR imaging. This method eliminates risks of contamination and biologic alteration of MSCs associated with ex vivo-labeling procedures.© RSNA, 2013Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130858/-/DC1.

  View details for DOI 10.1148/radiol.13130858

  View details for PubMedID 23850832

• Enhancing in vivo survival of adipose-derived stromal cells through bcl-2 overexpression using a minicircle vector. Stem cells translational medicine Hyun, J., Grova, M., Nejadnik, H., Lo, D., Morrison, S., Montoro, D., Chung, M., Zimmermann, A., Walmsley, G. G., Lee, M., Daldrup-Link, H., Wan, D. C., Longaker, M. T. 2013; 2 (9): 690-702

  Abstract

  Tissue regeneration using progenitor cell-based therapy has the potential to aid in the healing of a diverse range of pathologies, ranging from short-gut syndrome to spinal cord lesions. However, there are numerous hurdles to be overcome prior to the widespread application of these cells in the clinical setting. One of the primary barriers to effective stem cell therapy is the hostile environment that progenitor cells encounter in the clinical injury wound setting. In order to promote cellular survival, stem cell differentiation, and participation in tissue regeneration, relevant cells and delivery scaffolds must be paired with strategies to prevent cell death to ensure that these cells can survive to form de novo tissue. The Bcl-2 protein is a prosurvival member of a family of proteins that regulate the mitochondrial pathway of apoptosis. Using several strategies to overexpress the Bcl-2 protein, we demonstrated a decrease in the mediators of apoptosis in vitro and in vivo. This was shown through the use of two different clinical tissue repair models. Cells overexpressing Bcl-2 not only survived within the wound environment at a statistically significantly higher rate than control cells, but also increased tissue regeneration. Finally, we used a nonintegrating minicircle technology to achieve this in a potentially clinically applicable strategy for stem cell therapy.

  View details for DOI 10.5966/sctm.2013-0035

  View details for PubMedID 23934910

• Role of diffusion-weighted imaging in differentiating benign and malignant pediatric abdominal tumors. Pediatric radiology Gawande, R. S., Gonzalez, G., Messing, S., Khurana, A., Daldrup-Link, H. E. 2013; 43 (7): 836-845

  Abstract

  BACKGROUND: Solid malignant tumors are more highly cellular than benign lesions and hence have a restricted diffusion of water molecules. OBJECTIVE: To evaluate whether diffusion-weighted MR imaging (DWI) can differentiate between benign and malignant pediatric abdominal tumors. MATERIALS AND METHODS: We retrospectively analyzed DWI scans of 68 consecutive children with 39 benign and 34 malignant abdominal masses. To calculate the apparent diffusion coefficient (ADC) maps and ADC values, we used 1.5-T sequences at TR/TE/b-value of 5,250-7,500/54-64/b = 0, 500 and 3-T sequences at 3,500-4,000/66-73/b = 0, 500, 800. ADC values were compared between benign and malignant and between data derived at 1.5 tesla (T) and at 3 tesla magnetic field strength, using the Mann-Whitney-Wilcoxon test, ANOVA and a receiver operating curve (ROC) analysis. RESULTS: There was no significant difference in ADC values obtained at 1.5 T and 3 T (P = 0.962). Mean ADC values (× 10(-3) mm(2)/s) were 1.07 for solid malignant tumors, 1.6 for solid benign tumors, 2.9 for necrotic portions of malignant tumors and 3.1 for cystic benign lesions. The differences between malignant and benign solid tumors were statistically significant (P = 0.000025). ROC analysis revealed an optimal cut-off ADC value for differentiating malignant and benign solid tumors as 1.29 with excellent inter-observer reliability (alpha score 0.88). CONCLUSION: DWI scans and ADC values can contribute to distinguishing between benign and malignant pediatric abdominal tumors.

  View details for DOI 10.1007/s00247-013-2626-0

  View details for PubMedID 23666206

• Evaluation of the novel USPIO GEH121333 for MR imaging of cancer immune responses. Contrast media & molecular imaging Shi, Q., Pisani, L. J., Lee, Y. K., Messing, S., Ansari, C., Bhaumik, S., Lowery, L., Lee, B. D., Meyer, D. E., Daldrup-Link, H. E. 2013; 8 (3): 281-288

  Abstract

  Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n = 4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n = 4 each). Animals were monitored for 7 days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7 T scanner before and up to 72 h post-injection (p.i.) of GEH121333 (n = 10) or ferumoxytol (n = 9). Tumor R1 , R2 * relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1 , T2 and T2 *-weighted images at 1, 24, 48 and 72 h p.i. GEH121333 generated stronger tumor T2 * enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72 h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol. Copyright © 2013 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/cmmi.1526

  View details for PubMedID 23606432

  View details for PubMedCentralID PMC3662997

• Comparison of the diagnostic value of MR imaging and ophthalmoscopy for the staging of retinoblastoma EUROPEAN RADIOLOGY Khurana, A., Eisenhut, C. A., Wan, W., Ebrahimi, K. B., Patel, C., O'Brien, J. M., Yeom, K., Daldrup-Link, H. E. 2013; 23 (5): 1271-1280

  Abstract

  To compare the diagnostic value of magnetic resonance (MR) imaging and ophthalmoscopy for staging of retinoblastoma.MR and ophthalmoscopic images of 36 patients who underwent enucleation were evaluated retrospectively following institutional review board approval. Histopathology being the standard of reference, the sensitivity and specificity of both diagnostic modalities were compared regarding growth pattern, iris neoangiogenesis, retinal detachment, vitreous seeds and optic nerve invasion. Data were analysed via McNemar's test.Both investigations showed no significant difference in accuracy for the detection of different tumour growth patterns (P = 0.80). Vitreous seeding detection was superior by ophthalmoscopy (P < 0.001). For prelaminar optic nerve invasion, MR imaging showed similar sensitivity as ophthalmoscopy but increased specificity of 40 % (CI 0.12-0.74) vs. 20 % (0.03-0.56). MR detected optic nerve involvement past the lamina cribrosa with a sensitivity of 80 % (0.28-0.99) and a specificity of 74 % (0.55-0.88). The absence of optic nerve enhancement excluded histopathological infiltration, but the presence of optic nerve enhancement included a high number of false positives (22-24 %).Ophthalmoscopy remains the method of choice for determining extent within the globe while MR imaging is useful for evaluating extraocular tumour extension. Thus, both have their own strengths and contribute uniquely to the staging of retinoblastoma.• Ophthalmoscopy: method of choice for determining extent of retinoblastoma within the globe. • MR imaging provides optimal evaluation of extrascleral and extraocular tumour extension. • Positive enhancement of the optic nerve on MRI does not necessarily indicate involvement.

  View details for DOI 10.1007/s00330-012-2707-8

  View details for Web of Science ID 000317427500015

  View details for PubMedID 23160663

• Magnetic resonance imaging and tracking of stem cells. Methods in molecular biology (Clifton, N.J.) Nejadnik, H., Castillo, R., Daldrup-Link, H. E. 2013; 1052: 1-10

  Abstract

  To date, several stem cell labeling protocols have been developed, contributing to a fast growing and promising field of stem cell imaging by MRI (magnetic resonance imaging). Most of these methods utilize iron oxide nanoparticles (MION, SPIO, USPIO, VSIOP) for cell labeling, which provide negative (dark) signal effects on T2-weighted MR images. The following protocol describes stem cell labeling techniques with commercially available gadolinium chelates, which provide positive contrast on T1-weighted MR images, which can be advantageous for specific applications.

  View details for DOI 10.1007/7651_2013_16

  View details for PubMedID 23743862

• MR Imaging Features of Gadofluorine-Labeled Matrix-Associated Stem Cell Implants in Cartilage Defects PLOS ONE Nejadnik, H., Henning, T. D., Thuy Do, T., Sutton, E. J., Baehner, F., Horvai, A., Sennino, B., McDonald, D., Meier, R., Misselwitz, B., Link, T. M., Daldrup-Link, H. E. 2012; 7 (12)

  Abstract

  The purpose of our study was to assess the chondrogenic potential and the MR signal effects of GadofluorineM-Cy labeled matrix associated stem cell implants (MASI) in pig knee specimen.Human mesenchymal stem cells (hMSCs) were labeled with the micelle-based contrast agent GadofluorineM-Cy. Ferucarbotran-labeled hMSCs, non-labeled hMSCs and scaffold only served as controls. Chondrogenic differentiation was induced and gene expression and histologic evaluation were performed. The proportions of spindle-shaped vs. round cells of chondrogenic pellets were compared between experimental groups using the Fisher's exact test. Labeled and unlabeled hMSCs and chondrocytes in scaffolds were implanted into cartilage defects of porcine femoral condyles and underwent MR imaging with T1- and T2-weighted SE and GE sequences. Contrast-to-noise ratios (CNR) between implants and adjacent cartilage were determined and analyzed for significant differences between different experimental groups using the Kruskal-Wallis test. Significance was assigned for p<0.017, considering a Bonferroni correction for multiple comparisons.Collagen type II gene expression levels were not significantly different between different groups (p>0.017). However, hMSC differentiation into chondrocytes was superior for unlabeled and GadofluorineM-Cy-labeled cells compared with Ferucarbotran-labeled cells, as evidenced by a significantly higher proportion of spindle cells in chondrogenic pellets (p<0.05). GadofluorineM-Cy-labeled hMSCs and chondrocytes showed a positive signal effect on T1-weighted images and a negative signal effect on T2-weighted images while Ferucarbotran-labeled cells provided a negative signal effect on all sequences. CNR data for both GadofluorineM-Cy-labeled and Ferucarbotran-labeled hMSCs were significantly different compared to unlabeled control cells on T1-weighted SE and T2*-weighted MR images (p<0.017).hMSCs can be labeled by simple incubation with GadofluorineM-Cy. The labeled cells provide significant MR signal effects and less impaired chondrogenesis compared to Ferucarbotran-labeled hMSCs. Thus, GadoflurineM-Cy might represent an alternative MR cell marker to Ferucarbotran, which is not distributed any more in Europe or North America.

  View details for DOI 10.1371/journal.pone.0049971

  View details for Web of Science ID 000313236200022

  View details for PubMedCentralID PMC3520977

• Intravenous Ferumoxytol Allows Noninvasive MR Imaging Monitoring of Macrophage Migration into Stem Cell Transplants RADIOLOGY Khurana, A., Nejadnik, H., Gawande, R., Lin, G., Lee, S., Messing, S., Castaneda, R., Derugin, N., Pisani, L., Lue, T. F., Daldrup-Link, H. E. 2012; 264 (3): 803-811

  Abstract

  To develop a clinically applicable imaging technique for monitoring differential migration of macrophages into viable and apoptotic matrix-associated stem cell implants (MASIs) in arthritic knee joints.With institutional animal care and use committee approval, six athymic rats were injected with intravenous ferumoxytol (0.5 mmol iron per kilogram of body weight) to preload macrophages of the reticuloendothelial system with iron oxide nanoparticles. Forty-eight hours later, all animals received MASIs of viable adipose-derived stem cells (ADSCs) in an osteochondral defect of the right femur and mitomycin-pretreated apoptotic ADSCs in an osteochondral defect of the left femur. One additional control animal each received intravenous ferumoxytol and bilateral scaffold-only implants (without cells) or bilateral MASIs without prior ferumoxytol injection. All knees were imaged with a 7.0-T magnetic resonance (MR) imaging unit with T2-weighted fast spin-echo sequences immediately after, as well as 2 and 4 weeks after, matrix-associated stem cell implantation. Signal-to-noise ratios (SNRs) of viable and apoptotic MASIs were compared by using a linear mixed-effects model. MR imaging data were correlated with histopathologic findings.All ADSC implants showed a slowly decreasing T2 signal over 4 weeks after matrix-associated stem cell implantation. SNRs decreased significantly over time for the apoptotic implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 16.9, 10.9, and 6.7, respectively; P = .0004) but not for the viable implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 17.7, 16.2, and 15.7, respectively; P = .2218). At 4 weeks after matrix-associated stem cell implantation, SNRs of apoptotic ADSCs were significantly lower than those of viable ADSCs (mean, 6.7 vs 15.7; P = .0013). This corresponded to differential migration of iron-loaded macrophages into MASIs.Iron oxide loading of macrophages in the reticuloendothelial system by means of intravenous ferumoxytol injection can be utilized to monitor differential migration of bone marrow macrophages into viable and apoptotic MASIs in a rat model.

  View details for DOI 10.1148/radiol.12112393

  View details for PubMedID 22820731

• High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma RADIOGRAPHICS Rauschecker, A. M., Patel, C. V., Yeom, K. W., Eisenhut, C. A., Gawande, R. S., O'Brien, J. M., Ebrahimi, K. B., Daldrup-Link, H. E. 2012; 32 (5): 1307-1326

  Abstract

  Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.

  View details for DOI 10.1148/rg.325115176

  View details for Web of Science ID 000308632900010

  View details for PubMedID 22977020

• MR imaging of tumor-associated macrophages ONCOIMMUNOLOGY Daldrup-Link, H., Coussens, L. M. 2012; 1 (4)

  Abstract

  Tumor associated macrophages (TAMs) in breast cancers foster several aspects of tumor progression and metastasis, and represent a biomarker associated with an unfavorable clinical outcome. As new therapeutic agents selectively targeting leukocytes enter the clinic whose mechanism of action involves diminishing macrophage infiltration or presence in tumors, it becomes increasingly important to identify those tumors heavily infiltrated by TAMs, as well as monitoring TAM response to therapy. MR imaging with iron oxide nanoparticles enables noninvasive quantification of TAMs in tumors, and thus, provides an easily accessible ex vivo assessment of TAMs for prognosis and related treatment decisions.

  View details for DOI 10.4161/onci.19457

  View details for Web of Science ID 000316264200012

  View details for PubMedCentralID PMC3382895

• Dose Escalation Study of No-Carrier-Added I-131-Metaiodobenzylguanidine for Relapsed or Refractory Neuroblastoma: New Approaches to Neuroblastoma Therapy Consortium Trial JOURNAL OF NUCLEAR MEDICINE Matthay, K. K., Weiss, B., Villablanca, J. G., Maris, J. M., Yanik, G. A., DuBois, S. G., Stubbs, J., Groshen, S., Tsao-Wei, D., Hawkins, R., Jackson, H., Goodarzian, F., Daldrup-Link, H., Panigrahy, A., Towbin, A., Shimada, H., Barrett, J., LaFrance, N., Babich, J. 2012; 53 (7): 1155-1163

  Abstract

  (131)I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%-37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of (131)I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) (131)I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response.Eligible patients were 1-30 y old with resistant neuroblastoma, (131)I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA (131)I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA (131)I-MIBG (specific activity, 165 MBq/μg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA (131)I-MIBG was escalated from 444 to 777 MBq/kg (12-21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/μL within 28 d or platelets to greater than 20,000/μL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions.Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease.NCA (131)I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.

  View details for DOI 10.2967/jnumed.111.098624

  View details for Web of Science ID 000306164600033

  View details for PubMedID 22700000

• A photonic crystal cavity-optical fiber tip nanoparticle sensor for biomedical applications APPLIED PHYSICS LETTERS Shambat, G., Kothapalli, S. R., Khurana, A., Provine, J., Sarmiento, T., Cheng, K., Cheng, Z., Harris, J., Daldrup-Link, H., Gambhir, S. S., Vuckovic, J. 2012; 100 (21)

  View details for DOI 10.1063/1.4719520

  View details for Web of Science ID 000304489900085

• Magnetic Resonance Imaging of Ferumoxide-Labeled Mesenchymal Stem Cells in Cartilage Defects: In Vitro and In Vivo Investigations MOLECULAR IMAGING Henning, T. D., Gawande, R., Khurana, A., Tavri, S., Mandrussow, L., Golovko, D., Horvai, A., Sennino, B., McDonald, D., Meier, R., Wendland, M., Derugin, N., Link, T. M., Daldrup-Link, H. E. 2012; 11 (3): 197-209

  Abstract

  The purpose of this study was to (1) compare three different techniques for ferumoxide labeling of mesenchymal stem cells (MSCs), (2) evaluate if ferumoxide labeling allows in vivo tracking of matrix-associated stem cell implants (MASIs) in an animal model, and (3) compare the magnetic resonance imaging (MRI) characteristics of ferumoxide-labeled viable and apoptotic MSCs. MSCs labeled with ferumoxide by simple incubation, protamine transfection, or Lipofectin transfection were evaluated with MRI and histopathology. Ferumoxide-labeled and unlabeled viable and apoptotic MSCs in osteochondral defects of rat knee joints were evaluated over 12 weeks with MRI. Signal to noise ratios (SNRs) of viable and apoptotic labeled MASIs were tested for significant differences using t-tests. A simple incubation labeling protocol demonstrated the best compromise between significant magnetic resonance signal effects and preserved cell viability and potential for immediate clinical translation. Labeled viable and apoptotic MASIs did not show significant differences in SNR. Labeled viable but not apoptotic MSCs demonstrated an increasing area of T2 signal loss over time, which correlated to stem cell proliferation at the transplantation site. Histopathology confirmed successful engraftment of viable MSCs. The engraftment of iron oxide-labeled MASIs by simple incubation can be monitored over several weeks with MRI. Viable and apoptotic MASIs can be distinguished via imaging signs of cell proliferation at the transplantation site.

  View details for DOI 10.2310/7290.2011.00040

  View details for Web of Science ID 000307646000003

  View details for PubMedID 22554484

• Differentiation of Normal Thymus from Anterior Mediastinal Lymphoma and Lymphoma Recurrence at Pediatric PET/CT RADIOLOGY Gawande, R. S., Khurana, A., Messing, S., Zhang, D., Castaneda, R. T., Goldsby, R. E., Hawkins, R. A., Daldrup-Link, H. E. 2012; 262 (2): 613-622

  Abstract

  To evaluate the role of positron emission tomography (PET)/computed tomography (CT) in the differentiation of normal thymus from mediastinal lymphoma and lymphoma recurrence in pediatric patients.The study was approved by the institutional review board, and informed consent was waived. The study was HIPAA compliant. Two hundred eighty-two fluorine 18 fluorodeoxyglucose PET/CT studies in 75 pediatric oncology patients were reviewed retrospectively. Patients were divided into four groups: anterior mediastinal lymphoma (group A, n=16), anterior mediastinal lymphoma with subsequent recurrence (group B, n=5), lymphoma outside the mediastinum (group C, n=16), and other malignant tumors outside the thymus (group D, n=38). Analyses included measurements of the maximum anteroposterior and transverse dimensions of the anterior mediastinal mass or thymus on axial CT images and measurements of maximum standardized uptake values of anterior mediastinal mass, thymus (SUVt), and bone marrow at the level of the fifth lumbar vertebra (SUVb) on PET images. Quantitative parameters were compared by using an analysis of variance test.Mean prechemotherapy SUVt was 4.82 for group A, 8.45 for group B, 2.00 for group C, and 2.09 for group D. Mean postchemotherapy SUVt for group B was 4.74. Thymic rebound (mean SUVt, 2.89) was seen in 44% of patients at a mean interval of 10 months from the end of chemotherapy. The differences between prechemotherapy SUVt of mediastinal lymphoma and normal thymus and postchemotherapy SUVt of lymphoma recurrence and thymic rebound were highly significant (P<.001).SUVt is a sensitive predictor for differentiation of normal thymus or thymic rebound from mediastinal lymphoma. SUVt of 3.4 or higher is a strong predictor of mediastinal lymphoma.

  View details for DOI 10.1148/radiol.11110715

  View details for Web of Science ID 000300300200029

  View details for PubMedID 22157202

• Engineering stem cells for treatment of osteochondral defects SKELETAL RADIOLOGY Nejadnik, H., Daldrup-Link, H. E. 2012; 41 (1): 1-4

  View details for DOI 10.1007/s00256-011-1272-6

  View details for Web of Science ID 000297543700001

  View details for PubMedID 22072236

• Somatic Differentiation and MR Imaging of Magnetically Labeled Human Embryonic Stem Cells CELL TRANSPLANTATION Nejadnik, H., Henning, T. D., Castaneda, R. T., Boddington, S., Taubert, S., Jha, P., Tavri, S., Golovko, D., Ackerman, L., Meier, R., Daldrup-Link, H. E. 2012; 21 (12): 2555-2567

  Abstract

  Magnetic resonance (MR) imaging of superparamagnetic iron oxide (SPIO)-labeled stem cells offers a noninvasive evaluation of stem cell engraftment in host organs. Excessive cellular iron load from SPIO labeling, however, impairs stem cell differentiation. The purpose of this study was to magnetically label human embryonic stem cells (hESCs) via a reduced exposure protocol that maintains a significant MR signal and no significant impairment to cellular pluripotency or differentiation potential. hESCs were labeled by simple incubation with Food and Drug Administration-approved ferumoxides, using concentrations of 50- 200 µg Fe/ml and incubation times of 3-24 h. The most reduced exposure labeling protocol that still provided a significant MR signal comparable to accepted labeling protocols was selected for subsequent studies. Labeled hESCs were compared to unlabeled controls for differences in pluripotency as studied by fluorescence staining for SSEA-1, SSEA-4, TRA-60, and TRA-81 and in differentiation capacity as studied by quantitative real-time PCR for hOCT4, hACTC1, hSOX1, and hAFP after differentiation into embryoid bodies (EBs). Subsequent MR and microscopy imaging were performed to evaluate for cellular iron distribution and long-term persistence of the label. An incubation concentration of 50 µg Fe/ml and incubation time of 3 h demonstrated a significantly reduced exposure protocol that yielded an intracellular iron uptake of 4.50 ± 0.27 pg, an iron content comparable to currently accepted SPIO labeling protocols. Labeled and unlabeled hESCs showed no difference in pluripotency or differentiation capacity. Ferumoxide-labeled hESCs demonstrated persistent MR contrast effects as embryoid bodies for 21 days. Electron microscopy confirmed persistent lysosomal storage of iron oxide particles in EBs up to 9 days, while additional microscopy visualization confirmed the iron distribution within single and multiple EBs. Labeling hESCs with ferumoxides by this tailored protocol reduces exposure of cells to the labeling agent while allowing for long-term visualization with MR imaging and the retention of cellular pluripotency and differentiation potential.

  View details for DOI 10.3727/096368912X653156

  View details for Web of Science ID 000315001400002

  View details for PubMedID 22862886

• MR imaging features of gadofluorine-labeled matrix-associated stem cell implants in cartilage defects. PloS one Nejadnik, H., Henning, T. D., Do, T., Sutton, E. J., Baehner, F., Horvai, A., Sennino, B., McDonald, D., Meier, R., Misselwitz, B., Link, T. M., Daldrup-Link, H. E. 2012; 7 (12)

  Abstract

  The purpose of our study was to assess the chondrogenic potential and the MR signal effects of GadofluorineM-Cy labeled matrix associated stem cell implants (MASI) in pig knee specimen.Human mesenchymal stem cells (hMSCs) were labeled with the micelle-based contrast agent GadofluorineM-Cy. Ferucarbotran-labeled hMSCs, non-labeled hMSCs and scaffold only served as controls. Chondrogenic differentiation was induced and gene expression and histologic evaluation were performed. The proportions of spindle-shaped vs. round cells of chondrogenic pellets were compared between experimental groups using the Fisher's exact test. Labeled and unlabeled hMSCs and chondrocytes in scaffolds were implanted into cartilage defects of porcine femoral condyles and underwent MR imaging with T1- and T2-weighted SE and GE sequences. Contrast-to-noise ratios (CNR) between implants and adjacent cartilage were determined and analyzed for significant differences between different experimental groups using the Kruskal-Wallis test. Significance was assigned for p<0.017, considering a Bonferroni correction for multiple comparisons.Collagen type II gene expression levels were not significantly different between different groups (p>0.017). However, hMSC differentiation into chondrocytes was superior for unlabeled and GadofluorineM-Cy-labeled cells compared with Ferucarbotran-labeled cells, as evidenced by a significantly higher proportion of spindle cells in chondrogenic pellets (p<0.05). GadofluorineM-Cy-labeled hMSCs and chondrocytes showed a positive signal effect on T1-weighted images and a negative signal effect on T2-weighted images while Ferucarbotran-labeled cells provided a negative signal effect on all sequences. CNR data for both GadofluorineM-Cy-labeled and Ferucarbotran-labeled hMSCs were significantly different compared to unlabeled control cells on T1-weighted SE and T2*-weighted MR images (p<0.017).hMSCs can be labeled by simple incubation with GadofluorineM-Cy. The labeled cells provide significant MR signal effects and less impaired chondrogenesis compared to Ferucarbotran-labeled hMSCs. Thus, GadoflurineM-Cy might represent an alternative MR cell marker to Ferucarbotran, which is not distributed any more in Europe or North America.

  View details for DOI 10.1371/journal.pone.0049971

  View details for PubMedID 23251354

  View details for PubMedCentralID PMC3520977

• MR imaging of tumor-associated macrophages. Oncoimmunology Daldrup-Link, H., Coussens, L. M. 2012; 1 (4): 507–9

  Abstract

  Tumor associated macrophages (TAMs) in breast cancers foster several aspects of tumor progression and metastasis, and represent a biomarker associated with an unfavorable clinical outcome. As new therapeutic agents selectively targeting leukocytes enter the clinic whose mechanism of action involves diminishing macrophage infiltration or presence in tumors, it becomes increasingly important to identify those tumors heavily infiltrated by TAMs, as well as monitoring TAM response to therapy. MR imaging with iron oxide nanoparticles enables noninvasive quantification of TAMs in tumors, and thus, provides an easily accessible ex vivo assessment of TAMs for prognosis and related treatment decisions.

  View details for PubMedID 22754769

• Labeling human embryonic stem-cell-derived cardiomyocytes for tracking with MR imaging PEDIATRIC RADIOLOGY Castaneda, R. T., Boddington, S., Henning, T. D., Wendland, M., Mandrussow, L., Liu, S., Daldrup-Link, H. 2011; 41 (11): 1384-1392

  Abstract

  Human embryonic stem cells (hESC) can generate cardiomyocytes (CM), which offer promising treatments for cardiomyopathies in children. However, challenges for clinical translation result from loss of transplanted cell from target sites and high cell death. An imaging technique that noninvasively and repetitively monitors transplanted hESC-CM could guide improvements in transplantation techniques and advance therapies.To develop a clinically applicable labeling technique for hESC-CM with FDA-approved superparamagnetic iron oxide nanoparticles (SPIO) by examining labeling before and after CM differentiation.Triplicates of hESC were labeled by simple incubation with 50 μg/ml of ferumoxides before or after differentiation into CM, then imaged on a 7T MR scanner using a T2-weighted multi-echo spin-echo sequence. Viability, iron uptake and T2-relaxation times were compared between groups using t-tests.hESC-CM labeled before differentiation demonstrated significant MR effects, iron uptake and preserved function. hESC-CM labeled after differentiation showed no significant iron uptake or change in MR signal (P < 0.05). Morphology, differentiation and viability were consistent between experimental groups.hESC-CM should be labeled prior to CM differentiation to achieve a significant MR signal. This technique permits monitoring delivery and engraftment of hESC-CM for potential advancements of stem cell-based therapies in the reconstitution of damaged myocardium.

  View details for DOI 10.1007/s00247-011-2130-3

  View details for Web of Science ID 000296005400006

  View details for PubMedID 21594541

• Labeling Stem Cells with Ferumoxytol, an FDA-Approved Iron Oxide Nanoparticle JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Castaneda, R. T., Khurana, A., Khan, R., Daldrup-Link, H. E. 2011

  Abstract

  Stem cell based therapies offer significant potential for the field of regenerative medicine. However, much remains to be understood regarding the in vivo kinetics of transplanted cells. A non-invasive method to repetitively monitor transplanted stem cells in vivo would allow investigators to directly monitor stem cell transplants and identify successful or unsuccessful engraftment outcomes. A wide range of stem cells continues to be investigated for countless applications. This protocol focuses on 3 different stem cell populations: human embryonic kidney 293 (HEK293) cells, human mesenchymal stem cells (hMSC) and induced pluripotent stem (iPS) cells. HEK 293 cells are derived from human embryonic kidney cells grown in culture with sheared adenovirus 5 DNA. These cells are widely used in research because they are easily cultured, grow quickly and are easily transfected. hMSCs are found in adult marrow. These cells can be replicated as undifferentiated cells while maintaining multipotency or the potential to differentiate into a limited number of cell fates. hMSCs can differentiate to lineages of mesenchymal tissues, including osteoblasts, adipocytes, chondrocytes, tendon, muscle, and marrow stroma. iPS cells are genetically reprogrammed adult cells that have been modified to express genes and factors similar to defining properties of embryonic stem cells. These cells are pluripotent meaning they have the capacity to differentiate into all cell lineages. Both hMSCs and iPS cells have demonstrated tissue regenerative capacity in-vivo. Magnetic resonance (MR) imaging together with the use of superparamagnetic iron oxide (SPIO) nanoparticle cell labels have proven effective for in vivo tracking of stem cells due to the near microscopic anatomical resolution, a longer blood half-life that permits longitudinal imaging and the high sensitivity for cell detection provided by MR imaging of SPIO nanoparticles. In addition, MR imaging with the use of SPIOs is clinically translatable. SPIOs are composed of an iron oxide core with a dextran, carboxydextran or starch surface coat that serves to contain the bioreactive iron core from plasma components. These agents create local magnetic field inhomogeneities that lead to a decreased signal on T2-weighted MR images. Unfortunately, SPIOs are no longer being manufactured. Second generation, ultrasmall SPIOs (USPIO), however, offer a viable alternative. Ferumoxytol (FerahemeTM) is one USPIO composed of a non-stoichiometric magnetite core surrounded by a polyglucose sorbitol carboxymethylether coat. The colloidal, particle size of ferumoxytol is 17-30 nm as determined by light scattering. The molecular weight is 750 kDa, and the relaxivity constant at 2T MRI field is 58.609 mM(-1) sec(-1) strength. Ferumoxytol was recently FDA-approved as an iron supplement for treatment of iron deficiency in patients with renal failure. Our group has applied this agent in an "off label" use for cell labeling applications. Our technique demonstrates efficient labeling of stem cells with ferumoxytol that leads to significant MR signal effects of labeled cells on MR images. This technique may be applied for non-invasive monitoring of stem cell therapies in pre-clinical and clinical settings.

  View details for DOI 10.3791/3482

  View details for Web of Science ID 000209222200040

• MRI of Tumor-Associated Macrophages with Clinically Applicable Iron Oxide Nanoparticles CLINICAL CANCER RESEARCH Daldrup-Link, H. E., Golovko, D., Ruffell, B., DeNardo, D. G., Castaneda, R., Ansari, C., Rao, J., Tikhomirov, G. A., Wendland, M. F., Corot, C., Coussens, L. M. 2011; 17 (17): 5695-5704

  Abstract

  The presence of tumor-associated macrophages (TAM) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, noninvasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonanceI and clinically applicable iron oxide nanoparticles.F4/80-negative mammary carcinoma cells and F4/80-positive TAMs were incubated with iron oxide nanoparticles and were compared with respect to magnetic resonance signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced magnetic resonance imaging (MRI) up to 1 hour and 24 hours after injection. The tumor enhancement on MRIs was correlated with the presence and location of TAMs and nanoparticles by confocal microscopy.In vitro studies revealed that iron oxide nanoparticles are preferentially phagocytosed by TAMs but not by malignant tumor cells. In vivo, all tumors showed an initial contrast agent perfusion on immediate postcontrast MRIs with gradual transendothelial leakage into the tumor interstitium. Twenty-four hours after injection, all tumors showed a persistent signal decline on MRIs. TAM depletion via αCSF1 monoclonal antibodies led to significant inhibition of tumor nanoparticle enhancement. Detection of iron using 3,3'-diaminobenzidine-enhanced Prussian Blue staining, combined with immunodetection of CD68, localized iron oxide nanoparticles to TAMs, showing that the signal effects on delayed MRIs were largely due to TAM-mediated uptake of contrast agent.These data indicate that tumor enhancement with clinically applicable iron oxide nanoparticles may serve as a new biomarker for long-term prognosis, related treatment decisions, and the evaluation of new immune-targeted therapies.

  View details for DOI 10.1158/1078-0432.CCR-10-3420

  View details for Web of Science ID 000294477600020

  View details for PubMedID 21791632

  View details for PubMedCentralID PMC3166957

• Depicting Adoptive Immunotherapy for Prostate Cancer in an Animal Model with Magnetic Resonance Imaging MAGNETIC RESONANCE IN MEDICINE Meier, R., Golovko, D., Tavri, S., Henning, T. D., Knopp, C., Piontek, G., Rudelius, M., Heinrich, P., Wels, W. S., Daldrup-Link, H. 2011; 65 (3): 756-763

  Abstract

  Genetically modified natural killer (NK) cells that recognize tumor-associated surface antigens have recently shown promise as a novel approach for cancer immunotherapy. To determine NK cell therapy response early, a real-time, noninvasive method to quantify NK cell homing to the tumor is desirable. The purpose of this study was to evaluate if MR imaging could provide a noninvasive, in vivo diagnosis of NK cell accumulation in epithelial cell adhesion molecule (EpCAM)-positive prostate cancers in a rat xenograft model. Genetically engineered NK-92-scFv(MOC31)-ζ cells, which express a chimeric antigen receptor specific to the tumor-associated EpCAM antigen, and nontargeted NK-92 cells were labeled with superparamagnetic particles of iron-oxides (SPIO) ferumoxides. Twelve athymic rats with implanted EpCAM positive DU145 prostate cancers received intravenous injections of 1.5×10(7) SPIO labeled NK-92 and NK-92-scFv(MOC31)-ζ cells. EpCAM-positive prostate cancers demonstrated a progressive and a significant decline in contrast-to-noise-ratio data at 1 and 24 h after injection of SPIO-labeled NK-92-scFv(MOC31)-ζ cells. Conversely, tumor contrast-to-noise-ratio data did not change significantly after injection of SPIO-labeled parental NK-92 cells. Histopathology confirmed an accumulation of the genetically engineered NK-92-scFv(MOC31)-ζ cells in prostate cancers. Thus, the presence or absence of a tumor accumulation of therapeutic NK cells can be monitored with cellular MR imaging. EpCAM-directed, SPIO labeled NK-92-scFv(MOC31)-ζ cells accumulate in EpCAM-positive prostate cancers.

  View details for DOI 10.1002/mrm.22652

  View details for Web of Science ID 000287929800019

  View details for PubMedID 20928869

• Optical imaging of rheumatoid arthritis. International journal of clinical rheumatology Golovko, D., Meier, R., Rummeny, E., Daldrup-Link, H. 2011; 6 (1): 67-75

  Abstract

  Optical Imaging (OI) for rheumatoid arthritis is a novel imaging modality. With the high number of people affected by this disease, especially in western countries, the availability of OI as an early diagnostic imaging method is clinically highly relevant. In this article we describe the current techniques of OI and discuss potential future applications of this promising technology. Overall, we demonstrate that OI is a fast, inexpensive, noninvasive, nonionizing and accurate imaging modality. Furthermore, OI is a clinically applicable tool allowing for the early detection of inflammation and potentially facilitating the monitoring of therapy.

  View details for PubMedID 21826190

  View details for PubMedCentralID PMC3151026

• Labeling Human Mesenchymal Stem Cells with Fluorescent Contrast Agents: the Biological Impact MOLECULAR IMAGING AND BIOLOGY Boddington, S. E., Sutton, E. J., Henning, T. D., Nedopil, A. J., Sennino, B., Kim, A., Daldrup-Link, H. E. 2011; 13 (1): 3-9

  Abstract

  This study aims to determine the effect of human mesenchymal stem cell (hMSC) labeling with the fluorescent dye DiD and the iron oxide nanoparticle ferucarbotran on chondrogenesis.hMSCs were labeled with DiD alone or with DiD and ferucarbotran (DiD/ferucarbotran). hMSCs underwent confocal microscopy, optical imaging (OI), and magnetic resonance (MR) imaging. Chondrogenesis was induced by transforming growth factor-b and confirmed by histopathology and glycosaminoglycan (GAG) production. Data of labeled and unlabeled hMSCs were compared with a t test.Cellular uptake of DiD and ferucarbotran was confirmed with confocal microscopy. DiD labeling caused a significant fluorescence on OI, and ferucarbotran labeling caused a significant T2* effect on MR images. Compared to nonlabeled controls, progenies of labeled MSCs exhibited similar chondrocyte morphology after chondrogenic differentiation, but the labeled cells demonstrated significantly reduced GAG production (p < 0.05).DiD and DiD/ferucarbotran labeling of hMSC does not interfere with cell viability or morphologic differentiation into chondrocytes, but labeled cells exhibit significantly less GAG production compared to unlabeled cells.

  View details for DOI 10.1007/s11307-010-0322-0

  View details for Web of Science ID 000286395600002

  View details for PubMedID 20379785

• Labeling stem cells with ferumoxytol, an FDA-approved iron oxide nanoparticle. Journal of visualized experiments : JoVE Castaneda, R. T., Khurana, A., Khan, R., Daldrup-Link, H. E. 2011: e3482-?

  Abstract

  Stem cell based therapies offer significant potential for the field of regenerative medicine. However, much remains to be understood regarding the in vivo kinetics of transplanted cells. A non-invasive method to repetitively monitor transplanted stem cells in vivo would allow investigators to directly monitor stem cell transplants and identify successful or unsuccessful engraftment outcomes. A wide range of stem cells continues to be investigated for countless applications. This protocol focuses on 3 different stem cell populations: human embryonic kidney 293 (HEK293) cells, human mesenchymal stem cells (hMSC) and induced pluripotent stem (iPS) cells. HEK 293 cells are derived from human embryonic kidney cells grown in culture with sheared adenovirus 5 DNA. These cells are widely used in research because they are easily cultured, grow quickly and are easily transfected. hMSCs are found in adult marrow. These cells can be replicated as undifferentiated cells while maintaining multipotency or the potential to differentiate into a limited number of cell fates. hMSCs can differentiate to lineages of mesenchymal tissues, including osteoblasts, adipocytes, chondrocytes, tendon, muscle, and marrow stroma. iPS cells are genetically reprogrammed adult cells that have been modified to express genes and factors similar to defining properties of embryonic stem cells. These cells are pluripotent meaning they have the capacity to differentiate into all cell lineages. Both hMSCs and iPS cells have demonstrated tissue regenerative capacity in-vivo. Magnetic resonance (MR) imaging together with the use of superparamagnetic iron oxide (SPIO) nanoparticle cell labels have proven effective for in vivo tracking of stem cells due to the near microscopic anatomical resolution, a longer blood half-life that permits longitudinal imaging and the high sensitivity for cell detection provided by MR imaging of SPIO nanoparticles. In addition, MR imaging with the use of SPIOs is clinically translatable. SPIOs are composed of an iron oxide core with a dextran, carboxydextran or starch surface coat that serves to contain the bioreactive iron core from plasma components. These agents create local magnetic field inhomogeneities that lead to a decreased signal on T2-weighted MR images. Unfortunately, SPIOs are no longer being manufactured. Second generation, ultrasmall SPIOs (USPIO), however, offer a viable alternative. Ferumoxytol (FerahemeTM) is one USPIO composed of a non-stoichiometric magnetite core surrounded by a polyglucose sorbitol carboxymethylether coat. The colloidal, particle size of ferumoxytol is 17-30 nm as determined by light scattering. The molecular weight is 750 kDa, and the relaxivity constant at 2T MRI field is 58.609 mM(-1) sec(-1) strength. Ferumoxytol was recently FDA-approved as an iron supplement for treatment of iron deficiency in patients with renal failure. Our group has applied this agent in an "off label" use for cell labeling applications. Our technique demonstrates efficient labeling of stem cells with ferumoxytol that leads to significant MR signal effects of labeled cells on MR images. This technique may be applied for non-invasive monitoring of stem cell therapies in pre-clinical and clinical settings.

  View details for DOI 10.3791/3482

  View details for PubMedID 22083287

• Radiological-pathological correlation of pleomorphic liposarcoma of the anterior mediastinum in a 17-year-old girl PEDIATRIC RADIOLOGY Saeed, M., Plett, S., Kim, G. E., Daldrup-Link, H., Courtier, J. 2010; 40: 68-70

  View details for DOI 10.1007/s00247-010-1797-1

  View details for Web of Science ID 000285153000033

• Radiological-pathological correlation of pleomorphic liposarcoma of the anterior mediastinum in a 17-year-old girl. Pediatric radiology Saeed, M., Plett, S., Kim, G. E., Daldrup-Link, H., Courtier, J. 2010; 40: S68-70

  Abstract

  Liposarcoma is a soft-tissue sarcoma typically seen in adults. It is extremely rare in children. It most often occurs in the extremities or in the retroperitoneum. We present a very rare case of an anterior mediastinal liposarcoma of the pleomorphic subtype in a 17-year-old girl, along with radiological and pathological correlation. The location, patient age and histological subtype are exceedingly uncommon for this tumor.

  View details for DOI 10.1007/s00247-010-1797-1

  View details for PubMedID 20827472

• MR Signal Characteristics of Viable and Apoptotic Human Mesenchymal Stem Cells in Matrix-Associated Stem Cell Implants for Treatment of Osteoarthritis INVESTIGATIVE RADIOLOGY Nedopil, A., Klenk, C., Kim, C., Liu, S., Wendland, M., Golovko, D., Schuster, T., Sennino, B., McDonald, D. M., Daldrup-Link, H. E. 2010; 45 (10): 634-640

  Abstract

  To compare magnetic resonance (MR) signal characteristics of contrast agent-labeled apoptotic and viable human mesenchymal stem cells (hMSCs) in matrix-associated stem cell implants.hMSCs were labeled with Food and Drug Administration-approved ferumoxides nanoparticles. One group (A) remained untreated whereas a second group (B) underwent mitomycin C-induced apoptosis induction. Viability of group A and apoptosis of group B was confirmed by caspase-assays and terminal dUTP nick-end labeling (TUNEL) stains. Labeled viable hMSCs, unlabeled viable hMSCs, labeled apoptotic hMSCs, and unlabeled apoptotic hMSCs (n = 7 samples each) in an agarose scaffold were implanted into cartilage defects of porcine patellae specimens and underwent MR imaging at 7 T, using T1-weighted spin-echo sequences, T2-weighted spin-echo sequences, and T2*-weighted gradient-echo sequences. Signal-to-noise ratios (SNR) of the implants were calculated and compared between different experimental groups using linear mixed regression models.Ferumoxides-labeled hMSCs provided a strong negative T2 and T2*-enhancement. Corresponding SNR data of labeled hMSCs were significantly lower compared with unlabeled controls (P < 0.05). Apoptosis induction resulted in a significant signal decline of ferumoxides-labeled hMSC transplants on short echo time T2-weighted spinecho sequences. SNR data of labeled apoptotic hMSCs were significantly lower compared with labeled viable hMSCs (P < 0.05).Apoptosis of transplanted ferumoxides-labeled stem cells in cartilage defects can be visualized noninvasively by a significant signal decline on T2-weighted MR images. The described MR signal characteristics may serve as a noninvasive outcome measure for the assessment of matrix-associated stem cell implants in clinical practice. Additional studies are needed to further enhance the observed differences between viable and apoptotic cells, for example, by further optimizing the applied MR pulse sequence parameters or intracellular contrast agent concentration.

  View details for DOI 10.1097/RLI.0b013e3181ed566c

  View details for Web of Science ID 000282005200008

  View details for PubMedID 20808236

• In Vivo Magnetic Resonance Imaging and Optical Imaging Comparison of Viable and Nonviable Mesenchymal Stem Cells with a Bifunctional Label MOLECULAR IMAGING Sutton, E. J., Henning, T. D., Boddington, S., Demos, S., Krug, C., Meier, R., Kornak, J., Zhao, S., Baehner, R., Sharifi, S., Daldrup-Link, H. 2010; 9 (5): 278-290

  Abstract

  The purpose of this study was to compare viable and nonviable bilabeled mesenchymal stem cells (MSCs) in arthritic joints with magnetic resonance imaging (MRI) and optical imaging (OI). MSCs were labeled with ferucarbotran and DiD. MRI and OI of bilabeled cells were compared with controls. Six rats with arthritis received intra-articular injections of bilabeled viable MSCs into the right knee and nonviable MSCs into the left knee. Animals underwent MRI and OI preinjection and at 4, 24, 48, and 72 hours postinjection. The results were analyzed with a mixed random effects model and Fisher probability. Bilabeled MSCs showed increased MRI and OI signals compared to unlabeled controls (p < .0001). After intra-articular injection, bilabeled MSCs caused significant T2 and T2* effect on MRI and fluorescence on OI up to 72 hours postinjection (p < .05). There was no significant difference between viable and nonviable MSC signal in the knee joints; however, some of the viable cells migrated to an adjacent inflamed ankle joint (p < .05). Immunohistochemistry confirmed viable MSCs in right knee and ankle joints and nonviable MSCs in the left knee. Viable and nonviable cells could not be differentiated with MRI or OI signal intensity but were differentiated based on their ability to migrate in vivo.

  View details for DOI 10.2310/7290.2010.00029

  View details for Web of Science ID 000283457200005

  View details for PubMedID 20868628

• Unusual association of alveolar rhabdomyosarcoma with pancreatic metastasis: emerging role of PET-CT in tumor staging PEDIATRIC RADIOLOGY Jha, P., Froelich, A. M., McCarville, B., Navarro, O. M., Babyn, P., Goldsby, R., Daldrup-Link, H. 2010; 40 (8): 1380-1386

  Abstract

  Pancreatic metastases in childhood cancer have been rarely reported in the radiology literature although ample evidence exists in pathology reports for its occurrence in patients with alveolar rhabdomyosarcomas (RMS).Assess the occurrence of pancreatic metastases in alveolar rhabdomyosarcomas, increase awareness of this association and reassess current staging protocols.Three major oncology centers reviewed their records and imaging examinations. Patients' history and demographics, primary tumor site and histology, presence of tumor recurrence, and presence and location of other metastases were reviewed.Pancreatic metastases occurred in eight patients with alveolar RMS. Four of these presented at diagnosis and four with disease recurrence. In recurrent disease, the duration between the diagnosis of the primary tumor and pancreatic metastases varied from 8 months to 6 years (mean +/- SD: 2.38 +/- 2.49 years). In all patients who received PET scans, pancreatic metastases showed a marked FDG-uptake, but had variable detectability with CT. Pancreatic metastases were not associated with certain primary tumor locations or presence of other metastases, mandating an evaluation of the pancreas in all cases of alveolar rhabdomyosarcomas.Radiologists should be sensitized and actively evaluate the pancreas in patients with alveolar RMS. Optimizing CT and PET-CT protocols may increase the diagnostic yield.

  View details for DOI 10.1007/s00247-010-1572-3

  View details for Web of Science ID 000279478800009

  View details for PubMedID 20180103

• Monitoring of Natural Killer Cell Immunotherapy Using Noninvasive Imaging Modalities CANCER RESEARCH Jha, P., Golovko, D., Bains, S., Hostetter, D., Meier, R., Wendland, M. F., Daldrup-Link, H. E. 2010; 70 (15): 6109-6113

  Abstract

  Cancer immunotherapies can be guided by cellular imaging techniques, which can identify the presence or absence of immune cell accumulation in the tumor tissue in vivo and in real time. This review summarizes various new and evolving imaging techniques employed for tracking and monitoring of adoptive natural killer cell immunotherapies.

  View details for DOI 10.1158/0008-5472.CAN-09-3774

  View details for Web of Science ID 000280557500001

  View details for PubMedID 20631071

• Indocyanine Green-Enhanced Imaging of Antigen-Induced Arthritis With an Integrated Optical Imaging/Radiography System ARTHRITIS AND RHEUMATISM Meier, R., Krug, C., Golovko, D., Boddington, S., Piontek, G., Rudelius, M., Sutton, E. J., Baur-Melnyk, A., Jones, E. F., Daldrup-Link, H. E. 2010; 62 (8): 2322-2327

  Abstract

  To evaluate a combined indocyanine green-enhanced optical imaging/radiography system for the detection of arthritic joints in a rat model of antigen-induced arthritis.Arthritis of the knee and ankle joints was induced in 6 Harlan rats, using peptidoglycan-polysaccharide polymers. Three rats served as untreated controls. Optical imaging of the knee and ankle joints was done with an integrated optical imaging/radiography system before and up to 24 hours following intravenous injection of 10 mg/kg indocyanine green. The fluorescence signal intensities of arthritic and normal joints were compared for significant differences, using generalized estimating equation models. Specimens of knee and ankle joints were further processed and evaluated by histology.Immediately after administration, indocyanine green provided a significant increase in the fluorescence signal of arthritic joints compared with baseline values (P < 0.05). The fluorescence signal of arthritic joints was significantly higher compared with that of nonarthritic control joints at 1-720 minutes after intravenous injection (P < 0.05). Fusion of indocyanine green-enhanced optical imaging and radiography allowed for anatomic coregistration of the inflamed tissue with the associated joint. Hematoxylin and eosin staining confirmed marked synovial inflammation of arthritic joints and the absence of inflammation in control joints.Indocyanine green-enhanced optical imaging is a clinically applicable tool for detection of arthritic tissue. Using relatively high doses of indocyanine green, long-term enhanced fluorescence of arthritic joints can be achieved. This may facilitate simultaneous evaluations of multiple joints in a clinical setting. Fusion of indocyanine green-enhanced optical imaging scans with radiography increases anatomic resolution.

  View details for DOI 10.1002/art.27542

  View details for Web of Science ID 000282762100016

  View details for PubMedID 20506388

• Breast Cancers: MR Imaging of Folate-Receptor Expression with the Folate-Specific Nanoparticle P1133 RADIOLOGY Meier, R., Henning, T. D., Boddington, S., Tavri, S., Arora, S., Piontek, G., Rudelius, M., Corot, C., Daldrup-Link, H. E. 2010; 255 (2): 527-535

  Abstract

  To assess the capability of the folate receptor (FR)-targeted ultrasmall superparamagnetic iron oxide (USPIO) P1133 to provide FR-specific enhancement of breast cancers on magnetic resonance (MR) images.This study was approved by the institutional Animal Care and Use Committee. The FR-targeted contrast agent P1133 was incubated with various FR-positive human breast cancer cell lines, with and without free folic acid (FFA) as a competitor. Labeling efficiencies were evaluated with MR imaging and inductively coupled plasma mass spectrometry. Subsequently, six athymic rats with implanted FR-positive MDA-MB-231 breast cancers underwent MR imaging at 3 T before and up to 1 hour and 24 hours after injection of P1133. Six athymic rats with implanted FR-positive MDA-MB-231 cancers injected with the non-FR-targeted USPIO P904 and nine athymic rats with implanted FR-negative A549 lung cancers injected with P1133 (n = 6) or P904 (n = 3) served as controls. Data of the in vitro studies were compared for significant differences with the Wilcoxon test for two independent samples. Tumor signal-to-noise-ratios (SNRs) were compared between different experimental groups by using the Kruskal-Wallis test and were correlated with histopathologic findings. Differences with P < .05 were considered significant.FR-positive breast cancer cells showed a significant P1133 uptake which was inhibited by FFA. MDA-MB-231 cells showed the highest level of P1133 uptake and the strongest T2 effect on MR images. In vivo, all tumors showed an initial perfusion effect. At 24 hours after injection, only MDA-MB-231 tumors injected with P1133 showed significantly decreased SNR data compared with baseline data (P < .05). MR findings were confirmed by using histopathologic findings.The FR-targeted USPIO P1133 demonstrates a specific retention in FR-positive breast cancers. Because FR expression correlates with tumor aggressiveness and prognosis, persistent P1133 tumor enhancement may be used as a noninvasive indicator for tumors with poor outcome.

  View details for DOI 10.1148/radiol.10090050

  View details for Web of Science ID 000276976200026

  View details for PubMedID 20413763

• Accelerated stem cell labeling with ferucarbotran and protamine EUROPEAN RADIOLOGY Golovko, D. M., Henning, T., Bauer, J. S., Settles, M., Frenzel, T., Mayerhofer, A., Rummeny, E. J., Daldrup-Link, H. E. 2010; 20 (3): 640-648

  Abstract

  To develop and characterize a clinically applicable, fast and efficient method for stem cell labeling with ferucarbotran and protamine for depiction with clinical MRI.The hydrodynamic diameter, zeta potential and relaxivities of ferucarbotran and varying concentrations of protamine were measured. Once the optimized ratio was found, human mesenchymal stem cells (MSCs) were labeled at varying incubation times (1-24 h). Viability was assessed via Trypan blue exclusion testing. 150,000 labeled cells in Ficoll solution were imaged with T1-, T2- and T2*-weighted sequences at 3 T, and relaxation rates were calculated.Varying the concentrations of protamine allows for easy modification of the physicochemical properties. Simple incubation with ferucarbotran alone resulted in efficient labeling after 24 h of incubation while assisted labeling with protamine resulted in similar results after only 1 h. Cell viability remained unaffected. R2 and R2* relaxation rates were drastically increased. Electron microscopy confirmed intracellular iron oxide uptake in lysosomes. Relaxation times correlated with results from ICP-AES.Our results show internalization of ferucarbotran can be accelerated in MSCs with protamine, an approved heparin antagonist and potentially clinically applicable uptake-enhancing agent.

  View details for DOI 10.1007/s00330-009-1585-1

  View details for Web of Science ID 000274544800015

  View details for PubMedID 19756632

• Ectopic ureter associated with uterine didelphys and obstructed hemivagina: preoperative diagnosis by MRI PEDIATRIC RADIOLOGY Wang, Z. J., Daldrup-Link, H., Coakley, F. V., Yeh, B. M. 2010; 40 (3): 358-360

  Abstract

  Uterine didelphys with obstructed hemivagina and ipsilateral renal anomalies is a rare congenital malformation of the female urogenital tract. While the urinary anomalies almost always involve renal agenesis, we report a rare case of a 17-year-old girl with the malformation associated with ectopic ureteral insertion into the obstructed hemivagina, which was diagnosed preoperatively by MR imaging. To the best of our knowledge, preoperative MR imaging diagnosis of the ectopic ureter associated with this syndrome has not been previously reported. Accurate preoperative diagnosis of ectopic ureteral insertion associated with this syndrome is important for surgical planning.

  View details for DOI 10.1007/s00247-009-1454-8

  View details for Web of Science ID 000274386700012

  View details for PubMedID 19924410

• Labeling Human Embryonic Stem Cell-Derived Cardiomyocytes With Indocyanine Green for Noninvasive Tracking With Optical Imaging: An FDA-Compatible Alternative to Firefly Luciferase CELL TRANSPLANTATION Boddington, S. E., Henning, T. D., Jha, P., Schlieve, C. R., Mandrussow, L., DeNardo, D., Bernstein, H. S., Ritner, C., Golovko, D., Lu, Y., Zhao, S., Daldrup-Link, H. E. 2010; 19 (1): 55-65

  Abstract

  Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have demonstrated the ability to improve myocardial function following transplantation into an ischemic heart; however, the functional benefits are transient possibly due to poor cell retention. A diagnostic technique that could visualize transplanted hESC-CMs could help to optimize stem cell delivery techniques. Thus, the purpose of this study was to develop a labeling technique for hESCs and hESC-CMs with the FDA-approved contrast agent indocyanine green (ICG) for optical imaging (OI). hESCs were labeled with 0.5, 1.0, 2.0, and 2.5 mg/ml of ICG for 30, 45, and 60 min at 37 degrees C. Longitudinal OI studies were performed with both hESCs and hESC-CMs. The expression of surface proteins was assessed with immunofluorescent staining. hESCs labeled with 2 mg ICG/ml for 60 min achieved maximum fluorescence. Longitudinal studies revealed that the fluorescent signal was equivalent to controls at 120 h postlabeling. The fluorescence signal of hESCs and hESC-CMs at 1, 24, and 48 h was significantly higher compared to precontrast data (p < 0.05). Immunocytochemistry revealed retention of cell-specific surface and nuclear markers postlabeling. These data demonstrate that hESCs and hESC-CMs labeled with ICG show a significant fluorescence up to 48 h and can be visualized with OI. The labeling procedure does not impair the viability or functional integrity of the cells. The technique may be useful for assessing different delivery routes in order to improve the engraftment of transplanted hESC-CMs or other stem cell progenitors.

  View details for DOI 10.3727/096368909X

  View details for Web of Science ID 000276592500007

  View details for PubMedID 20370988

  View details for PubMedCentralID PMC2939828

• Implantation of ferumoxides labeled human mesenchymal stem cells in cartilage defects. Journal of visualized experiments : JoVE Nedopil, A. J., Mandrussow, L. G., Daldrup-Link, H. E. 2010

  Abstract

  The field of tissue engineering integrates the principles of engineering, cell biology and medicine towards the regeneration of specific cells and functional tissue. Matrix associated stem cell implants (MASI) aim to regenerate cartilage defects due to arthritic or traumatic joint injuries. Adult mesenchymal stem cells (MSCs) have the ability to differentiate into cells of the chondrogenic lineage and have shown promising results for cell-based articular cartilage repair technologies. Autologous MSCs can be isolated from a variety of tissues, can be expanded in cell cultures without losing their differentiation potential, and have demonstrated chondrogenic differentiation in vitro and in vivo(1, 2). In order to provide local retention and viability of transplanted MSCs in cartilage defects, a scaffold is needed, which also supports subsequent differentiation and proliferation. The architecture of the scaffold guides tissue formation and permits the extracellular matrix, produced by the stem cells, to expand. Previous investigations have shown that a 2% agarose scaffold may support the development of stable hyaline cartilage and does not induce immune responses(3). Long term retention of transplanted stem cells in MASI is critical for cartilage regeneration. Labeling of MSCs with iron oxide nanoparticles allows for long-term in vivo tracking with non-invasive MR imaging techniques(4). This presentation will demonstrate techniques for labeling MSCs with iron oxide nanoparticles, the generation of cell-agarose constructs and implantation of these constructs into cartilage defects. The labeled constructs can be tracked non-invasively with MR-Imaging.

  View details for DOI 10.3791/1793

  View details for PubMedID 20368696

• An optical imaging method to monitor stem cell migration in a model of immune-mediated arthritis OPTICS EXPRESS Sutton, E. J., Boddington, S. E., Nedopil, A. J., Henning, T. D., Demos, S. G., Baehner, R., Sennino, B., Lu, Y., Daldrup-Link, H. E. 2009; 17 (26): 24403-24413

  Abstract

  The objective of this work is to establish an optical imaging technique that would enable monitoring of the integration of mesenchymal stem cells (MSC) in arthritic joints. Our approach is based on first developing a labeling technique of MSC with the fluorescent dye DiD followed by tracking the cell migration kinetics from the spatial distribution of the DiD fluorescence in optical images (OI). The experimental approach involves first the in vitro OI of MSC labeled with DiD accompanied by fluorescence microscopy measurements to establish localization of the signal within the cells. Thereafter, DiD-labeled MSC were injected into polyarthritic, athymic rats and the signal localization within the experimental animals was monitored over several days. The experimental results indicate that DiD integrated into the cell membrane. DiD-labeled MSC localization in the arthritic ankle joints was observed with OI indicating that this method can be applied to monitor MSC in arthritic joints.

  View details for Web of Science ID 000273156200107

  View details for PubMedID 20052149

• Optical imaging of the peri-tumoral inflammatory response in breast cancer JOURNAL OF TRANSLATIONAL MEDICINE Sista, A. K., Knebel, R. J., Tavri, S., Johansson, M., DeNardo, D. G., Boddington, S. E., Kishore, S. A., Ansari, C., Reinhart, V., Coakley, F. V., Coussens, L. M., Daldrup-Link, H. E. 2009; 7

  Abstract

  Peri-tumoral inflammation is a common tumor response that plays a central role in tumor invasion and metastasis, and inflammatory cell recruitment is essential to this process. The purpose of this study was to determine whether injected fluorescently-labeled monocytes accumulate within murine breast tumors and are visible with optical imaging.Murine monocytes were labeled with the fluorescent dye DiD and subsequently injected intravenously into 6 transgenic MMTV-PymT tumor-bearing mice and 6 FVB/n control mice without tumors. Optical imaging (OI) was performed before and after cell injection. Ratios of post-injection to pre-injection fluorescent signal intensity of the tumors (MMTV-PymT mice) and mammary tissue (FVB/n controls) were calculated and statistically compared.MMTV-PymT breast tumors had an average post/pre signal intensity ratio of 1.8+/- 0.2 (range 1.1-2.7). Control mammary tissue had an average post/pre signal intensity ratio of 1.1 +/- 0.1 (range, 0.4 to 1.4). The p-value for the difference between the ratios was less than 0.05. Confocal fluorescence microscopy confirmed the presence of DiD-labeled cells within the breast tumors.Murine monocytes accumulate at the site of breast cancer development in this transgenic model, providing evidence that peri-tumoral inflammatory cell recruitment can be evaluated non-invasively using optical imaging.

  View details for DOI 10.1186/1479-5876-7-94

  View details for Web of Science ID 000272253600002

  View details for PubMedID 19906309

• Decreased aortic growth and middle aortic syndrome in patients with neuroblastoma after radiation therapy PEDIATRIC RADIOLOGY Sutton, E. J., Tong, R. T., Gillis, A. M., Henning, T. D., Weinberg, V. A., Boddington, S., Haas-Kogan, D. A., Matthay, K., Sha, V., Gooding, C., Coakley, F. V., Daldrup-Link, H. 2009; 39 (11): 1194-1202

  Abstract

  Long-term CT follow-up studies are required in pediatric patients who have received intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) to assess vascular toxicities and to determine the exact complication rate.To analyze with CT the effects of radiation therapy (RT) on the growth of the aorta in neuroblastoma patients.Abdominal CT scans of 31 patients with intraabdominal neuroblastoma (stage II-IV), treated with RT (20 IORT+/-EBRT, 11 EBRT alone), were analyzed retrospectively. The diameter of the abdominal aorta was measured before and after RT. These data were compared to normal and predicted normal aortic diameters of children, according to the model of Fitzgerald, Donaldson and Poznanski (aortic diameter in centimeters = 0.844 + 0.0599 x age in years), and to the diameters of a control group of children who had not undergone RT. Statistical analyses for the primary aims were performed using the chi-squared test, t-test, Mann-Whitney test, nonparametric Wilcoxon matched-pairs test and analysis of variance for repeated measures. Clinical files and imaging studies were evaluated for signs of late vascular complications of neuroblastoma patients who had received RT.The mean diameter before and after RT and the growth of the aorta were significantly lower than expected in patients with neuroblastoma (P<0.05 for each) and when compared to the growth in a control group with normal and nonirradiated aortas. Among the patients who had received RT, there was no difference due to the type of RT. Seven patients from the IORT+/-EBRT group developed vascular complications, which included hypertension (five), middle aortic syndrome (two), death due to mesenteric ischemia (one) and critical aortic stenosis, which required aortic bypass surgery (two).Patients with neuroblastoma who had received RT showed impaired growth of the abdominal aorta. Significant long-term vascular complications occurred in seven patients who received IORT+/-EBRT. Thus, CT evaluation of patients with neuroblastoma who receive RT should include not only reports of changes in tumor extension, but also documentation of perfusion, and the size and growth of the aorta and its branches over time.

  View details for DOI 10.1007/s00247-009-1351-1

  View details for Web of Science ID 000271028600008

  View details for PubMedID 19763559

  View details for PubMedCentralID PMC2765626

• MR Imaging of Pediatric Arthritis RADIOLOGIC CLINICS OF NORTH AMERICA Daldrup-Link, H. E., Steinbach, L. 2009; 47 (6): 939-?

  View details for DOI 10.1016/j.rcl.2009.08.003

  View details for Web of Science ID 000272163500006

• MR Imaging of Pediatric Arthritis MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA Daldrup-Link, H. E., Steinbach, L. 2009; 17 (3): 451-?

  Abstract

  The role of MR imaging in pediatric arthritis is to detect early manifestations of arthritis, evaluate the extent of disease, and monitor disease activity during treatment. More specifically, MR imaging can characterize the pediatric arthropathy based on typical imaging findings, detect early signs of synovitis and erosions, stage the severity of joint involvement, demonstrate associated internal derangement, monitor disease progression or treatment response, and evaluate for complications. This article discusses MR imaging findings of juvenile idiopathic arthritis, enthesis-related arthritis, juvenile psoriatic arthritis, and articular findings in collagen vascular diseases, septic arthritic, hemophilia, neuroarthropathy, and pseudoarthridities.

  View details for DOI 10.1016/j.mric.2009.03.002

  View details for Web of Science ID 000268294100006

  View details for PubMedID 19524196

• Relaxation Effects of Ferucarbotran-Labeled Mesenchymal Stem Cells at 1.5T and 3T: Discrimination of Viable from Lysed Cells MAGNETIC RESONANCE IN MEDICINE Henning, T. D., Wendland, M. F., Golovko, D., Sutton, E. J., Sennino, B., Malek, F., Bauer, J. S., McDonald, D. M., Daldrup-Link, H. 2009; 62 (2): 325-332

  Abstract

  Human mesenchymal stem cells (hMSCs) were labeled with Ferucarbotran by simple incubation and cultured for up to 14 d. Iron content was determined by spectrometry and the intracellular localization of the contrast agent uptake was studied by electron and confocal microscopy. At various time points after labeling, ranging from 1 to 14 d, samples with viable or lysed labeled hMSCs, as well as nonlabeled controls, underwent MRI. Spin-echo (SE) and gradient-echo (GE) sequences with multiple TRs and TEs were used at 1.5T and 3T on a clinical scanner. Spectrometry showed an initial iron oxide uptake of 7.08 pg per cell. Microscopy studies revealed lysosomal compartmentalization. Contrast agent effects of hMSCs were persistent for up to 14 d after labeling. A marked difference in the T(2) effect of compartmentalized iron oxides compared to free iron oxides was found on T(2)-weighted sequences, but not on T(2)*-weighted sequences. The observed differences may be explained by the loss of compartmentalization of iron oxide particles, the uniformity of distribution, and the subsequent increase in dephasing of protons on SE images. These results show that viable cells with compartmentalized iron oxides may-in principle-be distinguished from lysed cells or released iron oxides.

  View details for DOI 10.1002/mrm.22011

  View details for Web of Science ID 000268432400007

  View details for PubMedID 19353670

• The influence of ferucarbotran on the chondrogenesis of human mesenchymal stem cells CONTRAST MEDIA & MOLECULAR IMAGING Henning, T. D., Sutton, E. J., Kim, A., Golovko, D., Horvai, A., Ackerman, L., Sennino, B., McDonald, D., Lotz, J., Daldrup-Link, H. E. 2009; 4 (4): 165-173

  Abstract

  For in vivo applications of magnetically labeled stem cells, biological effects of the labeling procedure have to be precluded. This study evaluates the effect of different ferucarbotran cell labeling protocols on chondrogenic differentiation of human mesenchymal stem cells (hMSC) as well as their implications for MR imaging. hMSC were labeled with ferucarbotran using various protocols: cells were labeled with 100 microg Fe/ml for 4 and 18 h and additional samples were cultured for 6 or 12 days after the 18 h labeling. Supplementary samples were labeled by transfection with protamine sulfate. Iron uptake was quantified by ICP-spectrometry and labeled cells were investigated by transmission electron microscopy and by immunostaining for ferucarbotran. The differentiation potential of labeled cells was compared with unlabeled controls by staining with Alcian blue and Hematoxylin and Eosin, then quantified by measurements of glucosaminoglycans (GAG). Contrast agent effect at 3 T was investigated on days 1 and 14 of chondrogenic differentiation by measuring signal-to-noise ratios on T(2)-SE and T(2)*-GE sequences. Iron uptake was significant for all labeling protocols (p < 0.05). The uptake was highest after transfection with protamine sulfate (25.65 +/- 3.96 pg/cell) and lowest at an incubation time of 4 h without transfection (3.21 +/- 0.21 pg/cell). While chondrogenic differentiation was decreased using all labeling protocols, the decrease in GAG synthesis was not significant after labeling for 4 h without transfection. After labeling by simple incubation, chondrogenesis was found to be dose-dependent. MR imaging showed markedly lower SNR values of all labeled cells compared with the unlabeled controls. This contrast agent effect persisted for 14 days and the duration of differentiation. Magnetic labeling of hMSC with ferucarbotran inhibits chondrogenesis in a dose-dependent manner when using simple incubation techniques. When decreasing the incubation time to 4 h, inhibition of chondrogenesis was not significant.

  View details for DOI 10.1002/cmmi.276

  View details for Web of Science ID 000269597900002

  View details for PubMedID 19670250

• New Perspectives on Bone Marrow Contrast Agents and Molecular Imaging SEMINARS IN MUSCULOSKELETAL RADIOLOGY Daldrup-Link, H. E., Mohanty, A., Cuenod, C., Pichler, B., Link, T. 2009; 13 (2): 145-156

  Abstract

  Magnetic resonance (MR) imaging of bone marrow provides a noninvasive diagnosis of the vascularity, cell quantity, and composition of the normal and pathological bone marrow. This article reviews new and evolving techniques for bone marrow MR imaging with a special focus on translational and clinical applications. Evaluations of bone marrow perfusion with standard small molecular contrast agents and, more recently, with macromolecular contrast agents are currently being applied for therapy monitoring. Cell-specific contrast agents are expected to improve the sensitivity and specificity of bone marrow MR imaging. Novel cellular and molecular imaging techniques for the depiction of cell metabolism and specific biochemical pathways are discussed. Cell tracking techniques may allow specific diagnoses of inflammatory processes as well as monitoring of novel therapies based on stem cells. Future developments of fusion imaging techniques and bifunctional contrast agents are directed to combine comprehensive information about bone marrow structure and function with targeted and image-guided therapies.

  View details for DOI 10.1055/s-0029-1220885

  View details for Web of Science ID 000266502800008

  View details for PubMedID 19455477

• Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study 43rd Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Wagner, L. M., Villablanca, J. G., Stewart, C. F., Crews, K. R., Groshen, S., Reynolds, C. P., Park, J. R., Maris, J. M., Hawkins, R. A., Daldrup-Link, H. E., Jackson, H. A., Matthay, K. K. AMER SOC CLINICAL ONCOLOGY. 2009: 1290–96

  Abstract

  Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.Patients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea.Fourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m(2)/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng . hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression.This all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.

  View details for DOI 10.1200/JCO.2008.18.5918

  View details for Web of Science ID 000266193700028

  View details for PubMedID 19171709

• Pediatric liver tumors - a pictorial review EUROPEAN RADIOLOGY Jha, P., Chawla, S. C., Tavri, S., Patel, C., Gooding, C., Daldrup-Link, H. 2009; 19 (1): 209-219

  Abstract

  Hepatic masses constitute about 5-6% of all intra-abdominal masses in children. The majority of liver tumors in children are malignant; these malignant liver tumors constitute the third most common intra-abdominal malignancy in the pediatric age group after Wilms' tumor and neuroblastoma. Only about one third of the liver tumors are benign. A differential diagnosis of liver tumors in children can be obtained based on the age of the child, clinical information (in particular AFP) and imaging characteristics. The purpose of this review is to report typical clinical and imaging characteristics of benign and malignant primary liver tumors in children.

  View details for DOI 10.1007/s00330-008-1106-7

  View details for Web of Science ID 000262568000031

  View details for PubMedID 18682957

• Multiple Scalp Lesions in a Patient with Keratitis, Ichthyosis and Deafness Syndrome Mimicking Metastatic Squamous Cell Carcinoma on 18F-FDG PET/CT. Radiology case reports Kleis, M. A., Daldrup-Link, H., Goldsby, R., Hawkins, R. A., Franc, B. L. 2009; 4 (2): 218-?

  Abstract

  We report the case of a 17-year-old girl with keratitis, ichthyosis, and deafness (KID) syndrome. As a complication of her KID syndrome she developed squamous cell carcinoma at the left index finger. Additional clinical features were multiple soft tissue lesions over the scalp mimicking metastatic disease on 18F-FDG PET/CT. To our knowledge, this is the first case report about the uptake pattern of KID syndrome associated skin lesions on whole body PET/CT with 18F-FDG.

  View details for DOI 10.2484/rcr.v4i2.218

  View details for PubMedID 27307799

• Optical Imaging of Cellular Immunotherapy against Prostate Cancer MOLECULAR IMAGING Tavri, S., Jha, P., Meier, R., Henning, T. D., Mueller, T., Hostetter, D., Knopp, C., Johansson, M., Reinhart, V., Boddington, S., Sista, A., Wels, W. S., Daldrup-Link, H. E. 2009; 8 (1): 15-26

  Abstract

  The purpose of this study was to track fluorophore-labeled, tumor-targeted natural killer (NK) cells to human prostate cancer xenografts with optical imaging (OI). NK-92-scFv(MOC31)-zeta cells targeted to the epithelial cell adhesion molecule (EpCAM) antigen on prostate cancer cells and nontargeted NK-92 parental cells were labeled with the near-infrared dye DiD (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine). The fluorescence, viability, and cytotoxicity of the labeled cells were evaluated. Subsequently, 12 athymic rats with prostate cancer xenografts underwent OI scans before and up to 24 hours postinjection of DiD-labeled parental NK-92 cells or NK-92-scFv(MOC31)-zeta cells. The tumor fluorescence intensity was measured and compared between pre- and postinjection scans and between both groups using t-tests. OI data were confirmed with fluorescence microscopy. In vitro studies demonstrated a significant increase in the fluorescence of labeled cells compared with unlabeled controls, which persisted over a period of 24 hours without any significant change in the viability. In vivo studies demonstrated a significant increase in tumor fluorescence at 24 hours postinjection of tumor-targeted NK-92-scFv(MOC31)-zeta cells but not parental NK cells. Ex vivo OI scans and fluorescence microscopy confirmed a specific accumulation of NK-92-scFv(MOC31)-zeta cells but not parental NK cells in the tumors. Tumor-targeted NK-92-scFv(MOC31)-zeta cells could be tracked to prostate cancer xenografts with OI.

  View details for DOI 10.2310/7290.2009.00002

  View details for Web of Science ID 000263883600002

  View details for PubMedID 19344572

• Diagnostic value of PET/CT for the staging and restaging of pediatric tumors EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Kleis, M., Daldrup-Link, H., Matthay, K., Goldsby, R., Lu, Y., Schuster, T., Schreck, C., Chu, P. W., Hawkins, R. A., Franc, B. L. 2009; 36 (1): 23-36

  Abstract

  The objective of this retrospective study was to compare the diagnostic value of 2-[(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography ((18)F-FDG PET)/CT versus (18)F-FDG PET and CT alone for staging and restaging of pediatric solid tumors.Forty-three children and adolescents (19 females and 24 males; mean age, 15.2 years; age range, 6-20 years) with osteosarcoma (n = 1), squamous cell carcinoma (n = 1), synovial sarcoma (n = 2), germ cell tumor (n = 2), neuroblastoma (n = 2), desmoid tumor (n = 2), melanoma (n = 3), rhabdomyosarcoma (n = 5), Hodgkin's lymphoma (n = 7), non-Hodgkin-lymphoma (n = 9), and Ewing's sarcoma (n = 9) who had undergone (18)F-FDG PET/CT imaging for primary staging or follow-up of metastases were included in this study. The presence, location, and size of primary tumors was determined separately for PET/CT, PET, and CT by two experienced reviewers. The diagnosis of the primary tumor was confirmed by histopathology. The presence or absence of metastases was confirmed by histopathology (n = 62) or clinical and imaging follow-up (n = 238).The sensitivities for the detection of solid primary tumors using integrated (18)F-FDG PET/CT (95%), (18)F-FDG PET alone (73%), and CT alone (93%) were not significantly different (p > 0.05). Seventeen patients showed a total of 153 distant metastases. Integrated PET/CT had a significantly higher sensitivity for the detection of these metastases (91%) than PET alone (37%; p < 0.05), but not CT alone (83%; p > 0.05). When lesions with a diameter of less than 0.5 cm were excluded, PET/CT (89%) showed a significantly higher specificity compared to PET (45%; p < 0.05) and CT (55%; p < 0.05). In a sub-analysis of pulmonary metastases, the values for sensitivity and specificity were 90%, 14%, 82% and 63%, 78%, 65%, respectively, for integrated PET/CT, stand-alone PET, and stand-alone CT. For the detection of regional lymph node metastases, (18)F-FDG PET/CT, (18)F-FDG PET alone, and CT alone were diagnostically correct in 83%, 61%, and 42%. A sub-analysis focusing on the ability of PET/CT, PET, and CT to detect osseous metastases showed no statistically significant difference between the three imaging modalities (p > 0.05).Our study showed a significantly increased sensitivity of PET/CT over that of PET for the detection of distant metastases but not over that of CT alone. However, the specificity of PET/CT for the characterization of pulmonary metastases with a diameter > 0.5 cm and lymph node metastases with a diameter of <1 cm was significantly increased over that of CT alone.

  View details for DOI 10.1007/s00259-008-0911-1

  View details for Web of Science ID 000261422600004

  View details for PubMedID 18719909

• Detection of postoperative granulation tissue with an ICG-enhanced integrated OI-/X-ray System JOURNAL OF TRANSLATIONAL MEDICINE Meier, R., Boddington, S., Krug, C., Acosta, F. L., Thullier, D., Henning, T. D., Sutton, E. J., Tavri, S., Lotz, J. C., Daldrup-Link, H. E. 2008; 6

  Abstract

  The development of postoperative granulation tissue is one of the main postoperative risks after lumbar spine surgery. This granulation tissue may lead to persistent or new clinical symptoms or complicate a follow up surgery. A sensitive non-invasive imaging technique, that could diagnose this granulation tissue at the bedside, would help to develop appropriate treatments. Thus, the purpose of this study was to establish a fast and economic imaging tool for the diagnosis of granulation tissue after lumbar spine surgery, using a new integrated Optical Imaging (OI)/X-ray imaging system and the FDA-approved fluorescent contrast agent Indocyanine Green (ICG).12 male Sprague Dawley rats underwent intervertebral disk surgery. Imaging of the operated lumbar spine was done with the integrated OI/X-ray system at 7 and 14 days after surgery. 6 rats served as non-operated controls. OI/X-ray scans of all rats were acquired before and after intravenous injection of the FDA-approved fluorescent dye Indocyanine Green (ICG) at a dose of 1 mg/kg or 10 mg/kg. The fluorescence signal of the paravertebral soft tissues was compared between different groups of rats using Wilcoxon-tests. Lumbar spines and paravertebral soft tissues were further processed with histopathology.In both dose groups, ICG provided a significant enhancement of soft tissue in the area of surgery, which corresponded with granulation tissue on histopathology. The peak and time interval of fluorescence enhancement was significantly higher using 10 mg/kg dose of ICG compared to the 1 mg/kg ICG dose. The levels of significance were p < 0.05. Fusion of OI data with X-rays allowed an accurate anatomical localization of the enhancing granulation tissue.ICG-enhanced OI is a suitable technique to diagnose granulation tissue after lumbar spine surgery. This new imaging technique may be clinically applicable for postoperative treatment monitoring. It could be also used to evaluate the effect of anti-inflammatory drugs and may even allow evaluations at the bedside with new hand-held OI scanners.

  View details for DOI 10.1186/1479-5876-6-73

  View details for Web of Science ID 000262373600002

  View details for PubMedID 19038047

• Receptor imaging of pediatric tumors: clinical practice and new developments PEDIATRIC RADIOLOGY Daldrup-Link, H. E., Hawkins, R. A., Meier, R., Goldsby, R. E., Artemov, D. 2008; 38 (11): 1154-1161

  Abstract

  Pediatric cancers often have specific molecular fingerprints making them primary candidates for the development of targeted imaging techniques. Tumor-targeted tracers have the potential to substantially advance the sensitivity and specificity of imaging techniques by improving tumor detection and characterization. This article reviews various approaches to target tumors via specific tumor antigens, tumor cell surface receptors and specific surface receptors of the endothelial cells of the tumor vessels. These new applied molecular imaging techniques are expected to improve our knowledge of the biology of pediatric cancers and, ultimately, to help in the development of tailored diagnoses and therapies, which may ultimately lead to better individual long-term outcomes.

  View details for DOI 10.1007/s00247-008-0878-x

  View details for Web of Science ID 000259921200002

  View details for PubMedID 18483730

• Cell tracking with optical imaging EUROPEAN RADIOLOGY Sutton, E. J., Henning, T. D., Pichler, B. J., Bremer, C., Daldrup-Link, H. E. 2008; 18 (10): 2021-2032

  Abstract

  Adaptability, sensitivity, resolution and non-invasiveness are the attributes that have contributed to the longstanding use of light as an investigational tool and form the basis of optical imaging (OI). OI, which encompasses numerous techniques and methods, is rapid (<5 min), inexpensive, noninvasive, nontoxic (no radiation) and has molecular (single-cell) sensitivity, which is equal to that of conventional nuclear imaging and several orders of magnitude greater than MRI. This article provides a comprehensive overview of emerging applications of OI-based techniques for in vivo monitoring of new stem cell-based therapies. Different fluorochromes for cell labeling, labeling methods and OI-based cell-tracking techniques will be reviewed with respect to their technical principles, current applications and aims for clinical translation. Advantages and limitations of these new OI-based cell-tracking techniques will be discussed. Non-invasive mapping of cells labeled with fluorochromes or OI marker genes has the potential to evolve further within the clinical realm.

  View details for DOI 10.1007/s00330-008-0984-z

  View details for Web of Science ID 000259141900001

  View details for PubMedID 18506449

• Improved fluorescence of indocyanine green in vitro and in vivo after simple cooling procedures CONTRAST MEDIA & MOLECULAR IMAGING Boddington, S., Sutton, E. J., Jones, E., Purcell, D. D., Henning, T. D., Tavri, S., Meier, R., Sista, A., Fu, Y., Daldrup-Link, H. 2008; 3 (5): 191-197

  Abstract

  Indocyanine green (ICG) is a contrast agent used for detecting angiogenesis with optical imaging (OI). The purpose of this study was to investigate whether cooling procedures increase the signal yield of ICG with OI. Test samples of 0.05 and 0.02 mM ICG in 40% DMSO and 60% DMEM underwent OI at four different temperatures (5, 37, 55 and 75 degrees C). In addition, six athymic rats with an antigen-induced arthritis of the knee and ankle joints underwent OI before and after injection of ICG (10 mg/ml, dose 15 mg/kg) on two separate days with and without cooling of the joints. The fluorescent signals of the test samples and arthritic joints were measured and evaluated for significant differences before and after cooling with a t-test. In vitro studies showed a strong negative correlation between ICG temperature and fluorescent signal. The mean fluorescent signal of arthritic joints (measured in efficiency) was 0.345 before ICG-injection, 4.55 after ICG-injection and before cooling and 9.71 after ICG-injection and after cooling. The fluorescent signal enhancement of arthritic joints with ICG-enhanced OI images increased significantly after cooling (p = 0.02). The signal yield of ICG can be significantly increased by cooling the target pathology. The primary underlying cause of the temperature dependence of ICG is enhanced collisional quenching with increasing temperature. This simple cooling method may be immediately helpful to increase the fluorescence signal yield in current ICG-enhanced OI-studies in patients.

  View details for DOI 10.1002/cmmi.251

  View details for Web of Science ID 000261387900006

  View details for PubMedID 18973215

• Tracking of [F-18]FDG-labeled natural killer cells to HER2/neu-positive tumors NUCLEAR MEDICINE AND BIOLOGY Meier, R., Piert, M., Piontek, G., Rudelius, M., Oostendorp, R. A., Senekowitsch-Schmidtke, R., Henning, T. D., Wels, W. S., Uherek, C., Rummeny, E. J., Daldrup-Link, H. E. 2008; 35 (5): 579-588

  Abstract

  The objective of this study was to label the human natural killer (NK) cell line NK-92 with [(18)F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors.NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [(18)F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [(18)F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology.The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [(18)F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x10(6) [(18)F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x10(6) NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues.The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [(18)F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography.

  View details for DOI 10.1016/j.nucmedbio.2008.02.006

  View details for Web of Science ID 000257505500008

  View details for PubMedID 18589302

• MR imaging of ovarian tumors using folate-receptor-targeted contrast agents PEDIATRIC RADIOLOGY Wang, Z. J., Boddington, S., Wendland, M., Meier, R., Corot, C., Daldrup-Link, H. 2008; 38 (5): 529-537

  Abstract

  Because of its over-expression in many human tumors, the folate receptor (FR) is a promising target for tumor-specific imaging.To evaluate the uptake of FR-targeted gadolinium (P866) and iron-oxide (P1048) agents in an ovarian tumor model.FR-positive ovarian cancer cells (IGROV-1) were incubated with FR-targeted agents (P866 or P1048) in the absence or presence of competing free folate. Intracellular gadolinium or iron-oxide concentrations were measured. MR imaging of implanted ovarian tumors in rats was performed following injection of FR-targeted (P866 and P1048) and nontargeted (P1001 and P904) agents. Changes in longitudinal and transverse relaxation rates (DeltaR1 and DeltaR2), which were proportional to the contrast agent concentration in the tumors, were compared between tumors injected with FR-targeted and nontargeted agents.IGROV-1 cells showed uptake of P866 and P1048, which decreased with competing free folate. The DeltaR1 values were higher at 1 h following injection of P866 than following injection of P1001 (P < 0.05), indicating a higher amount of contrast agent retained in the tumor following P866 injection. There was a trend for higher DeltaR2 values at 48 h following injection of P1048 than following injection of P904, but it was not statistically significant (P = 0.09).Specific accumulation of the FR-targeted gadolinium agent P866 was suggested in an FR-positive ovarian tumor model, demonstrating the possibility of combining the specificity of receptor targeting with the improved anatomic resolution of MR imaging. This could improve diagnosis and treatment of FR-positive tumors.

  View details for DOI 10.1007/s00247-008-0764-6

  View details for Web of Science ID 000254751800005

  View details for PubMedID 18357444

• Imaging characteristics of DHOG, a hepatobiliary contrast agent for preclinical MicroCT in mice ACADEMIC RADIOLOGY Henning, T., Weber, A. W., Bauer, J. S., Meier, R., Carlsen, J. M., Sutton, E. J., Prevrhal, S., Ziegler, S. I., Feussner, H., Daldrup-Link, H. E., Rurnmeny, E. J. 2008; 15 (3): 342-349

  Abstract

  This study was performed to assess the imaging characteristics and pharmacokinetics of 1,3-Bis-[7-(3-amino-2,4,6-triiodophenyl)-heptanoyl]-2-oleoyl glycerol (DHOG, Fenestra LC), a hepatobiliary contrast agent for microCT.We investigated the abdomen of 18 female C3H mice in a MicroCAT II microCT scanner before contrast agent injection and at multiple time points up to 48 hours after intravenous injection of DHOG (1 g I/kg body weight). The contrast agent effect was determined quantitatively and dynamically by measuring pre- and postcontrast Hounsfield units (HU) of the liver, aorta, spleen, and kidneys. Based on additional phantom measurements, the reproducibility of lesion detection was estimated for different lesion sizes.DHOG caused a marked early postcontrast enhancement of blood in the aorta and a very high enhancement of the spleen, both slowly declined after 90 minutes. The liver parenchyma showed a slow contrast agent accumulation and clearly increased HU data between 3 and 7 hours after injection. No significant renal parenchymal enhancement or excretion was noticed. At early time points after administration, DHOG exhibits characteristics of a macromolecular contrast agent by demonstrating a blood pool effect. At later time points, DHOG provides a prolonged, marked liver enhancement on microCT images due to its specific liver uptake. For a lesion size of 1 mm diameter, the variability in between two scans was 27.7 HU (P < .05) and the variability for different planes of one scan was 19.8 HU (P < .05).DHOG yields a very good visualization of the liver and delineation of the surrounding structures with a long plateau. It is a very suitable contrast agent for liver imaging in mice for microCT imaging. The presented protocol provides a high reproducibility for lesion detection with a relatively low radiation dose.

  View details for DOI 10.1016/j.acra.2007.10.007

  View details for Web of Science ID 000253789000009

  View details for PubMedID 18280932

• Labeling stem cells with fluorescent dyes for non-invasive detection with optical imaging. Journal of visualized experiments : JoVE Boddington, S., Henning, T. D., Sutton, E. J., Daldrup-Link, H. E. 2008

  Abstract

  Optical imaging (OI) is an easy, fast and inexpensive tool for in vivo monitoring of new stem cell based therapies. The technique is based on ex vivo labeling of stem cells with a fluorescent dye, subsequent intravenous injection of the labeled cells and visualization of their accumulation in specific target organs or pathologies. The presented technique demonstrates how we label human mesenchymal stem cells (hMSC) by simple incubation with the lipophilic fluorescent dye DiD (C67H103CIN2O3S) and how we label human embryonic stem cells (hESC) with the FDA approved fluorescent dye Indocyanine Green (ICG). The uptake mechanism is via adherence and diffusion of the lypophilic dye across the phospholipid cell membrane bilayer. The labeling efficiency is usually improved if the cells are incubated with the dye in serum-free media as opposed to incubation in serum-containing media. Furthermore, the addition of the transfection agent Protamine Sulfate significantly improves contrast agent uptake.

  View details for DOI 10.3791/686

  View details for PubMedID 19066580

• Labeling hESCs and hMSCs with iron oxide nanoparticles for non-invasive in vivo tracking with MR imaging. Journal of visualized experiments : JoVE Henning, T. D., Boddington, S., Daldrup-Link, H. E. 2008

  Abstract

  In recent years, stem cell research has led to a better understanding of developmental biology, various diseases and its potential impact on regenerative medicine. A non-invasive method to monitor the transplanted stem cells repeatedly in vivo would greatly enhance our ability to understand the mechanisms that control stem cell death and identify trophic factors and signaling pathways that improve stem cell engraftment. MR imaging has been proven to be an effective tool for the in vivo depiction of stem cells with near microscopic anatomical resolution. In order to detect stem cells with MR, the cells have to be labeled with cell specific MR contrast agents. For this purpose, iron oxide nanoparticles, such as superparamagnetic iron oxide particles (SPIO), are applied, because of their high sensitivity for cell detection and their excellent biocompatibility. SPIO particles are composed of an iron oxide core and a dextran, carboxydextran or starch coat, and function by creating local field inhomogeneities, that cause a decreased signal on T2-weighted MR images. This presentation will demonstrate techniques for labeling of stem cells with clinically applicable MR contrast agents for subsequent non-invasive in vivo tracking of the labeled cells with MR imaging.

  View details for DOI 10.3791/685

  View details for PubMedID 19066574

• Long-term outcome and toxicities of intraoperative radiotherapy for high-risk neuroblastoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Gillis, A. M., Sutton, E., DeWitt, K. D., Matthay, K. K., Weinberg, V., Fisch, B. M., Chan, A., Gooding, C., Daldrup-Link, H., Wara, W. M., Farmer, D. L., Harrison, M. R., Haas-Kogan, D. 2007; 69 (3): 858-864

  Abstract

  To review a historical cohort of consecutively accrued patients with high-risk neuroblastoma treated with intraoperative radiotherapy (IORT) to determine the therapeutic effect and late complications of this treatment.Between 1986 and 2002, 31 patients with newly diagnosed high-risk neuroblastoma were treated with IORT as part of multimodality therapy. Their medical records were reviewed to determine the outcome and complications. Kaplan-Meier probability estimates of local control, progression-free survival, and overall survival at 36 months after diagnosis were recorded.Intraoperative radiotherapy to the primary site and associated lymph nodes achieved excellent local control at a median follow-up of 44 months. The 3-year estimate of the local recurrence rate was 15%, less than that of most previously published series. Only 1 of 22 patients who had undergone gross total resection developed recurrence at the primary tumor site. The 3-year estimate of local control, progression-free survival, and overall survival was 85%, 47%, and 60%, respectively. Side effects attributable to either the disease process or multimodality treatment were observed in 7 patients who developed either hypertension or vascular stenosis. These late complications resulted in the death of 2 patients.Intraoperative radiotherapy at the time of primary resection offers effective local control in patients with high-risk neuroblastoma. Compared with historical controls, IORT achieved comparable control and survival rates while avoiding many side effects associated with external beam radiotherapy in young children. Although complications were observed, additional analysis is needed to determine the relative contributions of the disease process and specific components of the multimodality treatment to these adverse events.

  View details for DOI 10.1016/j.ijrobp.2007.04.006

  View details for Web of Science ID 000249943000030

  View details for PubMedID 17517478

• Cell labeling with the positive MR contrast agent Gadofluorine M EUROPEAN RADIOLOGY Henning, T. D., Saborowski, O., Golovko, D., Boddington, S., Bauer, J. S., Fu, Y., Meier, R., Pietsch, H., Sennino, B., McDonald, D. M., Daldrup-Link, H. E. 2007; 17 (5): 1226-1234

  Abstract

  The purpose of this study was to label human monocytes with Gadofluorine M by simple incubation for subsequent cell depiction at 1.5 and 3 T. Gadofluorine M displays a high r(1) relaxivity and is spontaneously phagocytosed by macrophages. Human monocytes were incubated with Gadofluorine M-Cy at varying concentrations and incubation times and underwent MR imaging at 1.5 and 3 T at increasing time intervals after the labeling procedure. R1-relaxation rates and r1 relaxivities of the labeled cells and non-labeled controls were determined. Cellular contrast agent uptake was examined by fluorescence microscopy and quantified by ICP-AES. Efficient cell labeling was achieved after incubation of the cells with 25 mM Gd Gadofluorine M for 12 h, resulting in a maximal uptake of 0.3 fmol Gd/cell without impairment of cell viability. Fluorescence microscopy confirmed internalization of the fluorescent contrast agent by monocytes. The r1 relaxivity of the labeled cells was 137 mM(-1)s(-1) at 1.5 T and 80.46 mM(-1)s(-1) at 3 T. Imaging studies showed stable labeling for at least 7 days. Human monocytes can be effectively labeled for MR imaging with Gadofluorine M. Potential in vivo cell-tracking applications include targeting of inflammatory processes with Gadofluorine-labeled leukocytes or monitoring of stem cell therapies for the treatment of arthritis.

  View details for DOI 10.1007/s00330-006-0522-9

  View details for Web of Science ID 000246096000011

  View details for PubMedID 17206428

• MR imaging of antigen-induced arthritis with a new, folate receptor-targeted contrast agent CONTRAST MEDIA & MOLECULAR IMAGING Saborowski, O., Simon, G. H., Raatschen, H., Wendland, M. F., Fu, Y., Henning, T., Baehner, R., Corot, C., Chen, M., Daldrup-Link, H. E. 2007; 2 (2): 72-81

  Abstract

  The purpose of this study was to investigate if the new folate receptor-targeted Gd-chelate P866 may enhance immune-mediated arthritis. A monoarthritis was induced in the right knee of 15 Sprague-Dawley rats. MR imaging of both knees was performed at 2 T before and up to 2 h and 24 h after injection (p.i.) of P866 (n = 3 dose finding study and n = 6, 0.02 mmol Gd/kg), the non-FR targeted P866 analog P1001 (n = 3 at 24 h after P866-administration, 0.02 mmol Gd/kg) or Gd-DOTA (n = 6, 0.1 mmol Gd/kg). Pulse sequences comprised T(1)-SPGR 80 degrees /50 ms/1.7 ms (flip angle/TR/TE) and inversion recovery 10 degrees /3000 ms/1500 ms/50-3050, 10 000 ms (flip angle/TR/TE/TI) sequences. DeltaSI-data and T(1)-relaxation times of arthritic knees and contralateral normal knees were determined. Folate receptor expression was confirmed with histopathology. All three contrast agents showed an initial perfusion effect with significantly higher DeltaSI-data of arthritic knees compared with normal knees (p < 0.05). In addition, P866, but not P1001 or Gd-DOTA, showed a prolonged enhancement of the synovitis. Compared with precontrast values, the T(1)-relaxation times of inflamed synovia were significantly decreased at 2 h p.i. of P866 (p < 0.05), but not P1001 or Gd-DOTA (p > 0.05). Histopathology confirmed the presence of folate receptors in the inflamed joints, but not normal joints. Thus, results suggest a specific accumulation of the folate receptor-targeted Gd-chelate P866 in this arthritis model.

  View details for DOI 10.1002/cmmi.128

  View details for Web of Science ID 000246934800002

  View details for PubMedID 17385788

• MR imaging of therapy-induced changes of bone marrow EUROPEAN RADIOLOGY Daldrup-Link, H. E., Henning, T., Link, T. M. 2007; 17 (3): 743-761

  Abstract

  MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment.

  View details for DOI 10.1007/s00330-006-0404-1

  View details for Web of Science ID 000244192100018

  View details for PubMedID 17021706

• Macrophage specific MRI imaging for antigen induced arthritides. A potential new strategy for the diagnosis of rheumatoid arthritis RADIOLOGE Simon, G. H., Daldrup-Link, H. E., Rummeny, E. J. 2007; 47 (1): 43-?

  Abstract

  The present work describes the potential of iron oxides for the detection of macrophages in synovitis in experimental, antigen-induced arthritis.The pivotal role of macrophages in rheumatoid arthritis (RA) in humans and in antigen-induced arthritis (AIA) in animal models is discussed. The latter appear to be very similar in many aspects to the human RA. We show the potential for iron oxide-enhanced magnetic resonance imaging (MRI) to determine the macrophage content in the arthritic synovial membranes. The results of our own research, as well as those of other research groups, are presented and discussed.MRI after the intravenous (i.v.) administration of iron oxides enables the depiction of macrophage content in arthritic synovial membranes in AIA through the effects of the intracellular compartmentalisation of iron oxide particles. These effects can be demonstrated in 24-h delayed images after i.v. contrast application, on T2-weighted spin-echo or turbo-spin-echo sequences, and especially on T2*-weighted gradient-echo sequences. The signal effects are not only apparent in high field strength (4.7 Tesla) but also on 1.5 Tesla clinical scanners.The use of iron oxides enables the determination of the macrophage content in synovitis in animals with AIA. This parameter represents a potential marker to determine disease activity, and possibly represents a marker to evaluate the effectiveness of specific therapies in human RA. Current knowledge of iron oxide-enhanced MRI is limited to animal models. The clinical evaluation of this new method in patients with RA has not yet been performed. However, based on the considerations presented here, significant progress in the diagnostic work-up of RA can be expected.

  View details for DOI 10.1007/s00117-006-1453-9

  View details for Web of Science ID 000244402700007

  View details for PubMedID 17221243

• Optical imaging of experimental arthritis using allogeneic leukocytes labeled with a near-infrared fluorescent probe EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Simon, G. H., Daldrup-Link, H. E., Kau, J., Metz, S., Schlegel, J., Piontek, G., Saborowski, O., Demos, S., Duyster, J., Pichler, B. J. 2006; 33 (9): 998-1006

  Abstract

  The purpose of this study was to assess the feasibility of inflammation detection in an antigen-induced arthritis model using fluorescent leukocytes and optical imaging.Antigen-mediated monoarthritis was induced in the right knee of 12 Sprague-Dawley rats. Six rats remained untreated and six rats were treated with cortisone. All rats received ex vivo fluorescent-labeled rat leukocytes. Optical images of both knees were acquired before and at 5 min, 1 h, 4 h, and 24 h after cell injection. Images were evaluated qualitatively and quantitatively by calculating signal intensity ratios between the right arthritic (A) and contralateral normal (N) knee. A/N ratios were tested for significant differences between baseline values and values after cell injection using a paired t test as well as between the untreated and cortisone-treated group using an unpaired t test. Synovial specimens were processed and evaluated for labeled cells with fluorescence microscopy.At 4 h and 24 h p.i., the A/N ratios of untreated arthritic knees showed a significant signal increase compared with baseline values (p<0.05) and a significant difference compared with A/N ratios of cortisone-treated animals (p<0.05). Fluorescent microscopy confirmed the presence of labeled cells in the arthritic synovium.Inflammation in antigen-induced arthritis can be detected with ex vivo labeled allogenic leukocytes and optical imaging.

  View details for DOI 10.1007/s00259-006-0081-y

  View details for Web of Science ID 000239740600005

  View details for PubMedID 16770602

• MRI of arthritis: Comparison of ultrasmall superparamagnetic iron oxide vs. Gd-DTPA JOURNAL OF MAGNETIC RESONANCE IMAGING Simon, G. H., von Vopelius-Feldt, J., Wendland, M. F., Fu, Y. J., Piontek, G., Schlegel, J., Chen, M. H., Daldrup-Link, H. E. 2006; 23 (5): 720-727

  Abstract

  To compare the ability of the ultrasmall superparamagnetic iron oxide (USPIO) SHU555C vs. gadopentetate dimeglumine (Gd-DTPA) to detect antigen-induced monoarthritis with MRI.Twelve seven-week-old female rats with an antigen-induced monoarthritis of the right knee were randomly assigned to two groups. Animals in group I (N = 6) underwent MRI using T1-weighted gradient-echo sequences before injection and at 2, 9, 17, 25, 33, 40, 47, 55, and 63 minutes postinjection (p.i.) of Gd-DTPA on day 1, and before injection and at 3, 23, 43, and 123 minutes p.i. of SHU555C on day 2. Animals in group II (N = 6) were imaged before injection and at 3, 23, 43, and 123 minutes p.i. using identical sequences. Signal-to-noise ratios (SNRs) and relative enhancement (DeltaSI%) of arthritic and normal synovium were determined from region-of-interest (ROI) measurements in consensus reading by two experienced radiologists. Data were tested for significant differences between the two agents and between the arthritic and normal knees using a mixed-effect model and F-tests (P < 0.05). Joints were processed for histopathology as the gold standard.USPIO and Gd-DTPA showed significant enhancement differences (P < 0.001). USPIO provided a progressive and persistent enhancement of arthritic joints while Gd-DTPA provided an early and rapidly declining enhancement. Maximal enhancement in synovitis was 400% at 40-120 minutes p.i. of USPIO vs. 300% at two minutes p.i. of Gd-DTPA. USPIO provided a significant higher difference in enhancement between the arthritic and normal synovium than Gd-DTPA (P < 0.001). Histopathology confirmed marked inflammatory synovial changes in all arthritis-induced right knee joints and normal synovium in all left knee joints.Both USPIO and Gd-DTPA detect arthritis by positive T1-enhancement. Compared to standard Gd-DTPA, the USPIO SHU555C provides a comparable maximal T1-enhancement (at two minutes p.i for Gd-DTPA and between 43 and 123 minutes p.i. for SHU555C), but in addition it provides a prolonged T1-enhancement of synovitis and a higher difference between the relative enhancement of arthritic and normal synovium.

  View details for DOI 10.1002/jmri.20556

  View details for Web of Science ID 000237124800015

  View details for PubMedID 16557494

• T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical MR scanning EUROPEAN RADIOLOGY Simon, G. H., Bauer, J., Saborovski, O., Fu, Y. J., Corot, C., Wendland, M. F., Daldrup-Link, H. E. 2006; 16 (3): 738-745

  Abstract

  In this study we evaluated the effects of intracellular compartmentalization of the ultrasmall superparamagnetic iron oxide (USPIO) ferumoxtran-10 on its proton T1 and T2 relaxivities at 1.5 and 3T. Monocytes were labeled with ferumoxtran-10 by simple incubation. Decreasing quantities of ferumoxtran-10-labeled cells (2.5x10(7)-0.3x10(7) cells/ml) and decreasing concentrations of free ferumoxtran-10 (without cells) in Ficoll solution were evaluated with 1.5 and 3T clinical magnetic resonance (MR) scanners. Pulse sequences comprised axial spin echo (SE) sequences with multiple TRs and fixed TE and SE sequences with fixed TR and increasing TEs. Signal intensity measurements were used to calculate T1 and T2 relaxation times of all samples, assuming a monoexponential signal decay. The iron content in all samples was determined by inductively coupled plasma atomic emission spectrometry and used for calculating relaxivities. Measurements at 1.5T and 3T showed higher T1 and T2 relaxivity values of free extracellular ferumoxtran-10 as opposed to intracellularly compartmentalized ferumoxtran-10, under the evaluated conditions of homogeneously dispersed contrast agents/cells in Ficoll solution and a cell density of up to 2.5x10(7) cells/ml. At 3T, differences in T1-relaxivities between intra- and extracellular USPIO were smaller, while differences in USPIO T2-relaxivities were similar compared with 1.5T. In conclusion, cellular compartmentalization of ferumoxtran-10 changes proton relaxivity.

  View details for DOI 10.1007/s00330-005-0031-2

  View details for Web of Science ID 000235268900023

  View details for PubMedID 16308692

• Ferumoxtran-10-enhanced MR imaging of the bone marrow before and after conditioning therapy in patients with non-Hodgkin lymphomas EUROPEAN RADIOLOGY Metz, S., Lohr, S., Settles, M., Beer, A., Woertler, K., Rummeny, E., Daldrup-Link, H. E. 2006; 16 (3): 598-607

  Abstract

  To quantify permeability changes of the "blood-bone marrow barrier" (BMB) and to detect malignant bone marrow infiltrations before and after conditioning therapy for subsequent leukapheresis using ferumoxtran-10-enhanced magnetic resonance (MR) imaging. Twenty-two patients with malignant non-Hodgkin lymphomas (NHL), including 9 patients (group A) before and 13 patients (group B) after conditioning therapy, underwent MR of the spine before and after infusion of ferumoxtran-10 (0.045 mmol Fe/kg BW). Pulse sequences comprised dynamic T1-GE and pre- and post-contrast T1-SE and STIR sequences. Dynamic deltaSI-data were correlated with the quantity of mobilized CD34+ cells. In addition, the number of focal bone marrow lesions was compared before and after ferumoxtran-10 administration. Dynamic deltaSI-data were higher in group B than in group A, indicating an increased BMB permeability after conditioning therapy. However, deltaSI-data did not correlate with the quantity of mobilized CD34+ cells. Ferumoxtran-10-enhanced STIR images demonstrated a significant signal decline of the normal, non-neoplastic bone marrow and a significantly increased detection of focal neoplastic lesions compared to pre-contrast images (P<0.05). Ferumoxtran-10 depicted the bone marrow response to conditioning therapy by an increase in BMB-permeability, which, however, did not correlate with the number of mobilized CD34+ cells. Ferumoxtran-10 improved the detection of focal bone marrow lesions significantly (P<0.05).

  View details for DOI 10.1007/s00330-005-0045-9

  View details for Web of Science ID 000235268900007

  View details for PubMedID 16284770

• MRI of arthritis with the USPIOSHU555C: Optimization of T1 enhancement ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN Simon, G., Daldrup-Link, H., von Vopelius-Feldt, J., Wendland, M., Fu, Y., Schlegel, J., Rummeny, E. 2006; 178 (2): 200-206

  Abstract

  To optimize contrast agent dose and pulse sequence parameters in order to achieve a maximal T1 enhancement in arthritic knee joints with ultra small superparamagnetic iron oxides (USPIO)-enhanced MRI.Antigen-mediated arthritis was induced in the right knee of nine Sprague Dawley rats. The arthritic knee joint as well as the contralateral normal knee were investigated in a 2 Tesla MR scanner before as well as in short intervals up to 2 h after USPIO injection, using T1-weighted gradient echo (GE) sequences. Three rats each received intravenous injections of the new USPIO SHU 555 C (SH U 555 C, Schering AG, Berlin) at doses of 40, 100 and 200 micromol Fe/kg. Pulse sequence parameters of the GE-sequence were optimized by varying flip angles (alpha) and echo times (TE). Changes in signal intensities (SI) of the arthritic knee and contralateral normal knee were quantified as DeltaSI (%) = /([SIpost - SIpre] / SIpre) x 100 %/ and compared with histopathology.Histology of the arthritic knees demonstrated a marked inflammatory proliferation of the synovium. The USPIO SH U 555 C caused a significant increase in signal intensity of the arthritic joints on T1-weighted MR images (p < 0.05). This effect was optimized using a flip angle of 60-70 degrees, a minimal TE and a dose of 200 micromol Fe/kg. Visually the contralateral normal knee did not show any USPIO enhancement.Inflammation can be depicted with marked T1 enhancement by the USPIO SH U 555 C using high contrast agent doses and optimized MR pulse sequence parameters.

  View details for Web of Science ID 000235133400007

  View details for PubMedID 16435251

• Ultrasmall supraparamagnetic iron oxide-enhanced magnetic resonance imaging of antigen-induced arthritis - A comparative study between SHUSSSC, ferumoxtran-10, and ferumoxytol INVESTIGATIVE RADIOLOGY Simon, G. H., von Vopelius-Feldt, J., Fu, Y. J., Schlegel, J., Pinotek, G., Wendland, M. F., Chen, M. H., Daldrup-Link, H. E. 2006; 41 (1): 45-51

  Abstract

  We sought to compare the ability of 3 ultrasmall superparamagnetic iron oxides (USPIOs) to detect and characterize antigen-induced arthritis with MR imaging.A monoarthritis was induced in the right knee of 18 rats. The left knee served as a normal control. Knees underwent magnetic resonance (MR) imaging before, up to 2 hours, and 24 hours after injection (p.i.) of 200 mumol Fe/kg SHU 555 C (n= 6), ferumoxtran-10 (n = 6), or ferumoxytol (n = 6), using T2-2D-SE 100/20,40,60,80/90 (TR/TE/flipangle), T2*-3D-spoiled gradient recalled (SPGR) 100/15/38, and T1-3D-SPGR 50/1,7/60 sequences.Quantitative signal to noise ratio and DeltaSI data of arthritic knees on T1- and T2*-weighted MR images showed no significant differences between the 3 USPIOs (P > 0.05). At 2 hours p.i., SNR and DeltaSI data were significantly increased from baseline on T1-weighted images and significantly decreased on T2*-weighted images (P < 0.001). At 24 hours p.i., the T1-enhancement returned to baseline, whereas the T2*-enhancement remained significantly elevated (P < 0.001). Immunostains demonstrated an USPIO compartmentalization in macrophages in the arthritic synovium.Based on the relatively small number of animals in our study group, inflammation in antigen-induced arthritis can be equally detected and characterized with any of the three USPIOs evaluated.

  View details for Web of Science ID 000234240800007

  View details for PubMedID 16355039

• Imaging of tumor angiogenesis: Current approaches and future prospects CURRENT PHARMACEUTICAL DESIGN Daldrup-Link, H. E., Simon, G. H., Brasch, R. C. 2006; 12 (21): 2661-2672

  Abstract

  Tumor angiogenesis imaging should provide non-invasive assays of tumor vascular characteristics to supplement the now conventional diagnostic imaging goals of depicting tumor location, size, and morphology. This article will review the current status of angiogenesis imaging approaches, considering ultrasound, CT, MR, SPECT, PET and optical techniques with attention to their respective capabilities and limitations. As a group, these imaging methods have some potential to depict and quantify tumor microvascular features, including those considered to be functionally associated with tumor angiogenesis. Additionally, new molecule-specific imaging techniques may serve to depict those biochemical pathways and regulatory events that control blood vessel growth and proliferation. Non-invasive monitoring of anti-angiogenic therapies has great appeal and should find wide application for defining tumor microvascular and metabolic changes, because treatment-related changes in tumor morphology tend to occur rather late and are non-specific. Future developments are likely to include "fusion" or "hybrid" imaging methods. Superimposed data from MR imaging with spectroscopy, PET with CT, and PET with MR should be able to integrate advantages of different modalities yielding comprehensive information about tumor structure, function and microenvironment.

  View details for Web of Science ID 000238779600007

  View details for PubMedID 16842165

• Mixture model approach to tumor classification based on pharmacokinetic measures of tumor permeability JOURNAL OF MAGNETIC RESONANCE IMAGING Spilker, M. E., Seng, K. Y., Yao, A. A., Daldrup-Link, H. E., Shames, D. M., Brasch, R. C., Vicini, P. 2005; 22 (4): 549-558

  Abstract

  To categorize the disease severity of mammary tumors in an animal model through the application of a novel tumor permeability mixture model within a hierarchical modeling framework.Thirty-six rats with mammary tumors of varying grade were imaged via dynamic contrast-enhanced (CE) MRI using albumin-(Gd-DTPA)30. Time-dependent contrast agent concentration curves for blood and tumor tissue were obtained and a mathematical model of microvascular blood-tissue exchange was developed under the hypothesis that endothelial integrity is disrupted in a manner proportional to the degree of malignancy, with benign tumors showing no disruption of the vasculature endothelium. This permeability model was incorporated into a statistical model for the benign and malignant tumor subgroups that enabled automatic subject classification. The structural and statistical models were implemented using the software Nonlinear Mixed Effects Modeling (NONMEM) to statistically separate subjects into the two subgroups.Individual tumor classifications (as benign or malignant) were evaluated against the Scarff-Bloom-Richardson microscopic scoring method as applied to the tumor histology of each subject. The model-based classification resulted in 90.9% sensitivity, 92.9% specificity, and 91.7% accuracy.Mixture model analysis provides a robust method for subject classification without user intervention and bias. Although the present results are promising, additional research is needed to further evaluate this technique for diagnostic purposes.

  View details for DOI 10.1002/jmri.20412

  View details for Web of Science ID 000232317700014

  View details for PubMedID 16161077

• Ultrasmall superparamagnetic iron-oxide-enhanced MR imaging of normal bone marrow in rodents: original research original research. Academic radiology Simon, G. H., Raatschen, H., Wendland, M. F., von Vopelius-Feldt, J., Fu, Y., Chen, M., Daldrup-Link, H. E. 2005; 12 (9): 1190-1197

  Abstract

  The objective is to compare three different ultrasmall superparamagnetic iron oxides (USPIOs) for magnetic resonance (MR) imaging of normal bone marrow in rodents.Femoral bone marrow in 18 Sprague-Dawley rats was examined by using MR imaging before and up to 2 and 24 hours postinjection (PI) of 200 mumol of Fe/kg of SHU555C (n = 6), ferumoxtran-10 (n = 6), or ferumoxytol (n = 6), using T1-weighted (50 ms/1.7 ms/60 degrees = repetition time [TR]/echo time [TE]/flip angle) and T2*-weighted (100 ms/15 ms/38 degrees = TR/TE/flip angle) three-dimensional spoiled gradient recalled echo sequences. USPIO-induced bone marrow was evaluated qualitatively and quantified as signal-to-noise ratio (SNR) and change in signal intensity (DeltaSI) values. A mixed-effect model was fitted to the SNR and DeltaSI values, and differences among USPIOs were tested for significance by using F tests.At 2 hours PI, all three USPIOs showed marked positive signal enhancement on T1-weighted images and a corresponding marked signal loss on T2*-weighted images. At 24 hours PI, the T1 effect of all three USPIOs disappeared, whereas T2*-weighted images showed persistent signal loss on SHU555C and ferumoxytol-enhanced MR images, but not ferumoxtran-10-enhanced MR images. Corresponding SNR and DeltaSI values on T2*-weighted MR images at 24 hours PI were significantly different from baseline for SHU555C and ferumoxytol, but not ferumoxtran-10.All three USPIO contrast agents, ferumoxtran-10, ferumoxytol, and SHU555C, can be applied for MR imaging of bone marrow. Ferumoxtran-10 apparently reveals a different kinetic behavior in bone marrow than ferumoxytol and SHU555C.

  View details for PubMedID 16099684

• Ultrasmall superparamagnetic iron-oxide-enhanced MR imaging of normal bone marrow in rodents: Original research ACADEMIC RADIOLOGY Simon, G. H., Raatschen, H. J., Wendland, M. F., von Vopelius-Feldt, J., Fu, Y. J., Chen, M. H., Daldrup-Link, H. E. 2005; 12 (9): 1190-1197

  View details for DOI 10.1016/j.acra.2005.05.014

  View details for Web of Science ID 000231463500016

• Optimization of gadodiamide concentration for MR arthrography at 3 T AMERICAN JOURNAL OF ROENTGENOLOGY Masi, J. N., Newitt, D., Sell, C. A., Daldrup-Link, H., Steinbach, L., Majumdar, S., Link, T. M. 2005; 184 (6): 1754-1761

  Abstract

  The purpose of our study was to determine the optimal concentration of a gadolinium-based contrast agent (gadodiamide) for direct MR arthrography at 3 T compared with 1.5 T in an in vitro study.Optimized concentrations of gadolinium-based contrast agents for MR arthrography are similar at 3 and 1.5 T, although a slightly greater dilution may be useful at 3 T. Signal-to-noise ratio peak levels are significantly reduced by adding an iodinated contrast agent, relatively significantly more at 3 T than at 1.5 T.

  View details for Web of Science ID 000229328700008

  View details for PubMedID 15908526

• The choice of region of interest measures in contrast-enhanced magnetic resonance image characterization of experimental breast tumors INVESTIGATIVE RADIOLOGY Preda, A., Turetschek, K., Daldrup, H., FLOYD, E., Novikov, V., Shames, D. M., Roberts, T. P., Carter, W. O., Brasch, R. C. 2005; 40 (6): 349-354

  Abstract

  The objectives of this study were to determine if magnetic resonance (MR) estimates of quantitative tissue microvascular characteristics from regions of interest (ROI) limited to the tumor periphery provided a better correlation with tumor histologic grade than ROI defined for the whole tumor in cross-section.A metaanalysis was based on 98 quantitative MR image breast tumor characterizations acquired in 3 separate experimental studies using identical methods for tumor induction and contrast enhancement.The endothelial transfer coefficient (K) of albumin (Gd-DTPA)30 from the tumor periphery correlated (r = 0.784) significantly more strongly (P < 0.001) with the pathologic tumor grade than K derived from the whole tumor (r = 0.604). K estimates, either from the tumor periphery or from the whole tumor, correlated significantly more strongly with histologic grade (P < 0.01) than MR image estimates of fractional plasma volume (fPV) from either tumor periphery (r = 0.368) or whole tumor (r = 0.323).K estimates from the tumor periphery were the best of these measurable MR image microvascular characteristics for predicting the histologic grade.

  View details for Web of Science ID 000229352200005

  View details for PubMedID 15905721

• Detection of hepatocellular carcinoma: comparison of Gd-DTPA- and ferumoxides-enhanced MR imaging EUROPEAN RADIOLOGY Simon, G., Link, T. M., Wortler, K., Doebereiner, F., Schulte-Frohlinde, E., Daldrup-Link, H., Settles, M., Rummeny, E. J. 2005; 15 (5): 895-903

  Abstract

  The aim was to compare the diagnostic performance of dynamic Gd-DTPA- and ferumoxides-enhanced MRI for hepatocellular carcinoma (HCC). Twenty-five patients with chronic hepatitis or liver cirrhosis underwent both dynamic gadopentetate- and ferumoxides-enhanced MRI studies of the liver for HCC detection on the same day. MR data of both studies were retrospectively and independently analyzed. Two observers determined in consensus the grade of diffuse fibrotic liver changes (mild, moderate or severe) and the number of focal lesions. HCCs were confirmed by histology (n=22) and/or follow-up studies for at least six months (n=64). Differences in results obtained from both MR data sets were tested for significance with the McNemar's test (p<0.05). Ferumoxides-enhanced MR images detected 84 of 99 hepatic lesions, including 82 of 86 HCCs and 2 false positive, nonmalignant lesions, while Gd-DTPA-enhanced MR images detected 92 of 99 hepatic lesions, including 81 of 86 HCCs and 11 false positive, nonmalignant lesions. Sensitivity of MRI for detection of HCCs was not significantly different between ferumoxides-enhanced (95.3%; p>0.05) and Gd-DTPA-enhanced scans (94.2%). Gd-DTPA- and ferumoxides-enhanced MRI perform equally well for HCC detection. The majority of small hypervascular hepatic lesions, detected on dynamic Gd-DTPA-enhanced MRI but not on ferumoxides-enhanced MRI, represent no HCCs.

  View details for DOI 10.1007/s00330-005-2669-1

  View details for Web of Science ID 000229296900006

  View details for PubMedID 15800773

• Comparison of iron oxide labeling properties of hematopoietic progenitor cells from umbilical cord blood and from peripheral blood for subsequent in vivo tracking in a xenotransplant mouse model XXX. Academic radiology Daldrup-Link, H. E., Rudelius, M., Oostendorp, R. A., Jacobs, V. R., Simon, G. H., Gooding, C., Rummeny, E. J. 2005; 12 (4): 502-510

  Abstract

  To compare and optimize ferumoxides labeling of human hematopoietic progenitor cells from umbilical cord blood and from peripheral blood for subsequent in vivo tracking with a clinical 1.5 T MR scanner.Human hematopoietic progenitor cells, derived from umbilical cord blood or peripheral blood, were labeled with Ferumoxides by simple incubation or lipofection. Cellular iron uptake was quantified with spectrometry. Then, 3 x 10(7)-labeled cells were injected into the tail vein of 12 female nude Balb/c mice. The mice underwent magnetic resonance imaging before and 24 hours after injection. Precontrast and postcontrast signal intensities of liver, spleen, and bone marrow were measured and tested for significant differences with the t-test. Immunostains served as a histopathologic standard of reference.After labeling by simple incubation, only umbilical cord blood cells, but not peripheral blood cells, showed a significant iron uptake and could be tracked in vivo with magnetic resonance imaging. Using lipofection, both cell types could be tracked in vivo. A significant decline in signal intensity was observed in liver, spleen, and bone marrow at 24 hours after injection of efficiently labeled ferumoxides cells (P < .05). Histopathology proved the distribution of iron oxide-labeled cells to these organs.Hematopoietic progenitor cells from umbilical cord blood can be labeled by simple incubation with an Food and Drug Administration-approved magnetic resonance contrast agent with sufficient efficiency to provide an in vivo cell tracking at 1.5 T. Progenitor cells from peripheral blood need to be labeled with adjunctive transfection techniques to be depicted in vivo at 1.5 T.

  View details for PubMedID 15831425

• Hematopoietic progenitor cells from umbilical cord blood and from peripheral blood for subsequent in vivo tracking in a xenotransplant mouse model XXX ACADEMIC RADIOLOGY Daldrup-Link, H. E., Rudelius, M., Oostendorp, R. A., Jacobs, V. R., Simon, G. H., Gooding, C., Rummeny, E. J. 2005; 12 (4): 502-510

  View details for DOI 10.1016/j.acra.2004.12.021

  View details for Web of Science ID 000228415300015

• Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: In vivo monitoring with 1.5-T MR imaging equipment 89th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America (RSNA) Daldrup-Link, H. E., Rudelius, M., Piontek, G., Metz, S., Brauer, R., Debus, G., Corot, C., Schlegel, J., Link, T. M., Peschel, C., Rummeny, E. J., Oostendorp, R. A. RADIOLOGICAL SOC NORTH AMERICA. 2005: 197–205

  Abstract

  To evaluate the use of clinical 1.5-T magnetic resonance (MR) imaging equipment to depict the in vivo distribution of iron oxide-labeled human hematopoietic progenitor cells in athymic mice.This study was approved by the ethical committee, and all women had given consent to donate umbilical cord blood for research. Twenty athymic female Balb/c mice underwent MR imaging before and 1, 4, 24, and 48 hours after intravenous injection of (1-3) x 10(7) human hematopoietic progenitor cells labeled with the superparamagnetic iron oxide particles ferumoxides through simple incubation (n = 10) or P7228 through lipofection (n = 10). Fifteen female Balb/c control mice were examined after intravenous injection of the pure contrast agents (n = 6 for both probes) or nonlabeled cells (n = 3). Signal intensities of liver, spleen, and bone marrow on MR images obtained before and after injection were measured and compared for significant differences by using the t test. MR imaging data were compared with the results of immunostaining against human CD31(+) cells and against the coating of the contrast agents; these results served as the standard of reference.Ferumoxides was internalized into more mature CD34(-) cells but not into CD34(+) stem cells, while P7228 liposomes were internalized into both CD34(-) and CD34(+) cells. After injection of iron oxide-labeled hematopoietic cells, a significant decrease in MR signal intensity was observed in liver and spleen at 1, 4, 24, and 48 hours after injection (P < .05) and in the bone marrow at 24 and 48 hours after injection (P < .05). The signal intensity decrease in bone marrow was significantly stronger after injection of iron oxide-labeled cells compared to controls that received injections of the pure contrast agent (P < .05). Results of histopathologic examination confirmed homing of iron oxide-labeled human progenitor cells in the murine recipient organs.The in vivo distribution of intravenously administered iron oxide-labeled hematopoietic progenitor cells can be monitored with 1.5-T MR imaging equipment.

  View details for DOI 10.1148/radiol.2341031236

  View details for Web of Science ID 000225864800027

  View details for PubMedID 15618382

• In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging EUROPEAN RADIOLOGY Daldrup-Link, H. E., Meier, R., Rudelius, M., Piontek, G., Piert, M., Metz, S., Settles, M., Uherek, C., Wels, W., Schlegel, J., Rummeny, E. J. 2005; 15 (1): 4-13

  Abstract

  The purpose of this study is to optimize labeling of the human natural killer (NK) cell line NK-92 with iron-oxide-based contrast agents and to monitor the in vivo distribution of genetically engineered NK-92 cells, which are directed against HER2/neu receptors, to HER2/neu positive mammary tumors with magnetic resonance (MR) imaging. Parental NK-92 cells and genetically modified HER2/neu specific NK-92-scFv(FRP5)-zeta cells, expressing a chimeric antigen receptor specific to the tumor-associated ErbB2 (HER2/neu) antigen, were labeled with ferumoxides and ferucarbotran using simple incubation, lipofection and electroporation techniques. Labeling efficiency was evaluated by MR imaging, Prussian blue stains and spectrometry. Subsequently, ferucarbotran-labeled NK-92-scFv(FRP5)-zeta (n=3) or parental NK-92 cells were intravenously injected into the tail vein of six mice with HER2/neu-positive NIH 3T3 mammary tumors, implanted in the mammary fat pad. The accumulation of the cells in the tumors was monitored by MR imaging before and 12 and 24 h after cell injection (p.i.). MR data were correlated with histopathology. Both the parental NK-92 and the genetically modified NK-92-scFv(FRP5)-zeta cells could be labeled with ferucarbotran and ferumoxides by lipofection and electroporation, but not by simple incubation. The intracellular cytoplasmatic iron-oxide uptake was significantly higher after labeling with ferucarbotran than ferumoxides (P<0.05). After intravenous injection of 5 x 10(6) NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, MR showed a progressive signal decline in HER2/neu-positive mammary tumors at 12 and 24 h (p.i.). Conversely, injection of 5 x 10(6) parental NK-92 control cells, not directed against HER2/neu receptors, did not cause significant signal intensity changes of the tumors. Histopathology confirmed an accumulation of the former, but not the latter cells in tumor tissue. The human natural killer cell line NK-92 can be efficiently labeled with clinically applicable iron-oxide contrast agents, and the accumulation of these labeled cells in murine tumors can be monitored in vivo with MR imaging. This MR cell tracking technique may be applied to monitor NK-cell based immunotherapies in patients in order to assess the presence and extent of NK-cell tumor accumulations and, thus, to determine therapy response early and non-invasively.

  View details for DOI 10.1007/s00330-004-2526-7

  View details for Web of Science ID 000227354900001

  View details for PubMedID 15616814

• Capacity of human monocytes to phagocytose approved iron oxide MR contrast agents in vitro EUROPEAN RADIOLOGY Metz, S., Bonaterra, G., Rudelius, M., Settles, M., Rummeny, E. J., Daldrup-Link, H. E. 2004; 14 (10): 1851-1858

  Abstract

  To evaluate the capacity of human monocytes to phagocytose various approved iron oxide based magnetic resonance (MR) contrast agents and to optimize in vitro labeling of these cells. Human monocytes were incubated with two superparamagnetic iron oxide particles (SPIO) as well as two ultrasmall SPIO (USPIO) at varying iron oxide concentrations and incubation times. Iron uptake in monocytes was proven by histology, quantified by atomic emission absorption spectrometry and depicted with T2* weighted fast field echo (FFE) MR images at 1.5 T. Additionally, induction of apoptosis in iron oxide labeled monocytes was determined by YO-PRO-1 staining. Cellular iron uptake was significantly (P<0.01) higher after incubation with SPIO compared with USPIO. For SPIO, the iron oxide uptake was significantly (P<0.01) higher after incubation with the ionic Ferucarbotran as compared with the non-ionic Ferumoxides. Efficient cell labeling was achieved after incubation with Ferucarbotran at concentrations > or = 500 microg Fe/ml and incubation times > or = 1 h, resulting in a maximal iron oxide uptake of up to 50 pg Fe/cell without impairment of cell viability. In vitro labeling of human monocytes for MR imaging is most effectively obtained with the approved SPIO Ferucarbotran. Potential subsequent in vivo cell tracking applications comprise, e.g. specific targeting of inflammatory processes.

  View details for DOI 10.1007/s00330-004-2405-2

  View details for Web of Science ID 000226576500017

  View details for PubMedID 15249981

• Cell tracking with gadophrin-2: a bifunctional contrast agent for MR imaging, optical imaging, and fluorescence microscopy EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Daldrup-Link, H. E., Rudelius, M., Metz, S., Piontek, G., Pichler, B., Settles, M., Heinzmann, U., Schlegel, J., Oostendorp, R. A., Rummeny, E. J. 2004; 31 (9): 1312-1321

  Abstract

  The purpose of this study was to assess the feasibility of use of gadophrin-2 to trace intravenously injected human hematopoietic cells in athymic mice, employing magnetic resonance (MR) imaging, optical imaging (OI), and fluorescence microscopy. Mononuclear peripheral blood cells from GCSF-primed patients were labeled with gadophrin-2 (Schering AG, Berlin, Germany), a paramagnetic and fluorescent metalloporphyrin, using established transfection techniques with cationic liposomes. The labeled cells were evaluated in vitro with electron microscopy and inductively coupled plasma atomic emission spectrometry. Then, 1x10(6)-3x10(8) labeled cells were injected into 14 nude Balb/c mice and the in vivo cell distribution was evaluated with MR imaging and OI before and 4, 24, and 48 h after intravenous injection (p.i.). Five additional mice served as controls: three mice were untreated controls and two mice were investigated after injection of unlabeled cells. The contrast agent effect was determined quantitatively for MR imaging by calculating signal-to-noise-ratio (SNR) data. After completion of in vivo imaging studies, fluorescence microscopy of excised organs was performed. Intracellular cytoplasmatic uptake of gadophrin-2 was confirmed by electron microscopy. Spectrometry determined an uptake of 31.56 nmol Gd per 10(6) cells. After intravenous injection, the distribution of gadophrin-2 labeled cells in nude mice could be visualized by MR, OI, and fluorescence microscopy. At 4 h p.i., the transplanted cells mainly distributed to lung, liver, and spleen, and 24 h p.i. they also distributed to the bone marrow. Fluorescence microscopy confirmed the distribution of gadophrin-2 labeled cells to these target organs. Gadophrin-2 is suited as a bifunctional contrast agent for MR imaging, OI, and fluorescence microscopy and may be used to combine the advantages of each individual imaging modality for in vivo tracking of intravenously injected hematopoietic cells.

  View details for DOI 10.1007/s00259-004-1484-2

  View details for Web of Science ID 000223532200013

  View details for PubMedID 15138719

• Decrease in tumor apparent permeability-surface area product to a MRI macromolecular contrast medium following angiogenesis inhibition with correlations to cytotoxic drug accumulation MICROCIRCULATION Daldrup-Link, H. E., Okuhata, Y., Wolfe, A., Srivastav, S., Oie, S., FERRARA, N., Cohen, R. L., Shames, D. M., Brasch, R. C. 2004; 11 (5): 387-396

  Abstract

  New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (K(PS)) in tumors to a macromolecular contrast medium (MMCM), to follow changes in K(PS) induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin.Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)(30)) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate K(PS). These estimates of K(PS) were correlated with cytotoxic drug accumulations in the tumors.Anti-VEGF treatment reduced K(PS) to MMCM in tumor tissue from 0.013 mL h(-1) cm(-3) (n = 9) at baseline to 0.003 mL h(-1) cm(-3) (n = 9) 24 h later (p <.05). The K(PS) values correlated significantly (r(2) =.78; p <.0001) with the tumor cisplatin accumulation. No correlation (r(2) =.001; p =.89) was found between K(PS) and tumor accumulation of the substantially smaller 5-FU molecule.MMCM-enhanced MRI can be used to detect and estimate changes in K(PS) to this contrast agent following a single dose of anti-VEGF antibody. The decline in K(PS) induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration.

  View details for DOI 10.1080/10739680490457665

  View details for Web of Science ID 000222086100001

  View details for PubMedID 15280064

• Quantification of breast tumor microvascular permeability with feruglose-enhanced MR imaging: Initial phase II multicenter trial RADIOLOGY Daldrup-Link, H. E., Rydland, J., Helbich, T. H., Bjornerud, A., Turetschek, K., Kvistad, K. A., Kaindl, E., Link, T. M., Staudacher, K., Shames, D., Brasch, R. C., Haraldseth, O., Rummeny, E. J. 2003; 229 (3): 885-892

  Abstract

  To investigate use of the macromolecular contrast agent feruglose for differentiating and grading of human benign and malignant breast tumors on the basis of their microvascular characteristics.Sixty-three women with 63 primary breast lesions were examined with dynamic T1-weighted gradient-echo magnetic resonance (MR) imaging after intravenous injection of feruglose. A two-compartment unidirectional kinetic model applied to the dynamic data yielded estimates of the endothelial transfer coefficient, KPS, and the fractional plasma volume of the tumors. These MR imaging-derived parameters were correlated with the histologic tumor grade and quantified according to the Scarff-Bloom-Richardson (SBR) score by means of Pearson product moment correlation analyses. Differences between malignant and nonmalignant breast lesions with respect to KPS for feruglose were evaluated by means of the chi2 test and by calculating the sensitivity, specificity, and positive and negative predictive values.Histologic analysis revealed 26 benign and 37 malignant tumors. A moderate yet statistically significant correlation between KPS and SBR score was found (R = 0.496, P <.001). No significant correlation was observed between fractional plasma volume and SBR score (R = 0.085, P =.507). The KPS values were zero for 19 (73%) of the 26 benign tumors and were greater than zero for 27 (73%) of the 37 carcinomas. This distribution was significantly different (chi2 = 13.035, P =.001). With the criterion KPS > 0 in carcinomas, sensitivity was 0.73, specificity was 0.73, and the positive predictive value was 0.79.Quantitative measures of tumor microvascular permeability can be used for breast tumor characterization. The probability of breast tumor microvascular hyperpermeability to be associated with malignancy is 79%.

  View details for DOI 10.1148/radiol.2293021045

  View details for Web of Science ID 000186717700037

  View details for PubMedID 14576446

• Macromolecular contrast medium (feruglose) versus small molecular contrast medium (gadopentetate) enhanced magnetic resonance imaging: Differentiation of benign and malignant breast lesions ACADEMIC RADIOLOGY Daldrup-Link, H. E., Kaiser, A., Helbich, T., Werner, M., Bjornerud, A., Link, T. M., Rummeny, E. J. 2003; 10 (11): 1237-1246

  Abstract

  To compare the diagnostic performance of the blood pool agent feruglose and the standard extracellular contrast agent gadopentetate in their abilities to differentiate benign and malignant breast tumors.Fourteen women, aged 35-77 years (mean, 55 years), with 19 breast lesions underwent dynamic fast field echo 14/1/30 degrees (TR/TE/alpha) magnetic resonance imaging of the breast after bolus injection of feruglose (Clariscan; Amersham Health, Amersham, UK: dose, 2 mg Fe/kg) and an additional, comparative gadopentetate (dose, 0.2 mmol gadolinium/kg)-enhanced fast field echo 10/4/30 degrees (TR/TE/alpha) magnetic resonance study within 1-11 days (mean, 4.8 days) before or after the feruglose study. All breast tumors were surgically excised within 1-6 days (mean, 2.5 days) after completion of the magnetic resonance studies. Data were analyzed by measuring quantitative enhancement data and qualitatively by categorizations of the shape of the tumor enhancement curves. Group differences between quantitative data of the two contrast agents and between benign and malignant tumors were evaluated using a two-tailed paired-sample t test. Differences in curve type distribution between benign and malignant tumors were tested with the chi2 test.Histopathology showed a spectrum of 10 benign and nine malignant breast lesions: five mastopathies, two fibroadenomas, two chronic inflammations, and one papillomatosis, as well as five invasive ductal carcinomas and four invasive lobular carcinomas. Substantial differences were observed between feruglose- and gadopentetate-enhanced images: the mean tumor deltaSI(%) peak enhancement and wash-in rate were significantly higher for gadopentetate- as compared with feruglose-enhanced images (P < .05). Using either contrast agent, morphologic enhancement characteristics showed a considerable overlap between benign and malignant breast lesions. However, the kinetic enhancement profiles of benign and malignant lesions were significantly different based on feruglose-enhanced data (chi2 = 9.017; P = .0027) but not gadopentetate-enhanced data (chi2 = 2.239; P = .3264).Compared with gadopentetate, the new blood pool agent feruglose provided an improved characterization of the evaluated breast lesions; however, at the cost of weaker overall tumor enhancement.

  View details for DOI 10.1016/S1076-6332(03)00248-4

  View details for Web of Science ID 000186307500004

  View details for PubMedID 14626298

• Targeting of hematopoietic progenitor cells with MR contrast agents RADIOLOGY Daldrup-Link, H. E., Rudelius, M., Oostendorp, R. A., Settles, M., Piontek, G., Metz, S., Rosenbrock, H., Keller, U., Heinzmann, U., Rummeny, E. J., Schlegel, J., Link, T. M. 2003; 228 (3): 760-767

  Abstract

  To label human hematopoietic progenitor cells with various magnetic resonance (MR) imaging contrast agents and to obtain 1.5-T MR images of them.Hematopoietic progenitor cells, labeled with ferumoxides, ferumoxtran, magnetic polysaccharide nanoparticles-transferrin, P7228 liposomes, and gadopentetate dimeglumine liposomes underwent MR imaging with T1- and T2-weighted spin-echo and fast field-echo sequences. Data were analyzed by measuring MR signal intensities and R1 and R2* relaxation rates of labeled cells and nonlabeled control cells. Mean quantitative data for the various contrast agent groups were assessed for significant differences compared with control cells by means of the Scheffe test. As a standard of reference, MR imaging data were compared with electron microscopic and spectrometric data.For all contrast agents, intracellular cytoplasm uptake was demonstrated with electron microscopy and was quantified with spectrometry. When compared with nonlabeled control cells, progenitor cells labeled with iron oxides showed significantly (P <.05) increased R2*. Cells labeled with gadopentetate dimeglumine liposomes showed significantly increased R1. Detection thresholds were 5 x 10(5) cells for gadopentetate dimeglumine liposomes and ferumoxtran, 2.5 x 10(5) cells for ferumoxides and P7228 liposomes, and 1 x 10(5) cells for magnetic polysaccharide nanoparticles-transferrin.Hematopoietic progenitor cells can be labeled with MR contrast agents and can be depicted with a standard 1.5-T MR imager.

  View details for DOI 10.1148/radiol.2283020322

  View details for Web of Science ID 000184966400025

  View details for PubMedID 12881578

• Highly efficient paramagnetic labelling of embryonic and neuronal stem cells EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Rudelius, M., Daldrup-Link, H. E., Heinzmann, U., Piontek, G., Settles, M., Link, T. M., Schlegel, J. 2003; 30 (7): 1038-1044

  Abstract

  Recent developments in stem cell and gene therapy will require methods to monitor stem cell survival and integration repeatedly and non-invasively with a high temporal and spatial resolution in vivo. The aim of this study was to visualise embryonic and neuronal stem cells with standard contrast agents using a conventional clinical 1.5-Tesla scanner. We therefore modified standard transfection protocols including lipofection (Lipofectin and Lipofectamine) and calcium phosphate transfection for the efficient uptake of paramagnetic particles [gadolinium-diethylene triamine penta-acetic acid (Gd-DTPA)] in stem cells. Using this approach we obtained intracellular labelling efficiencies of up to 83%. Neither the proliferation capacity nor the differentiation efficiency was affected. Identical differentiation of labelled and unlabelled embryonic and neuronal cells was observed. The established labelling techniques used in this study displayed high labelling efficiencies in embryonic and neuronal stem cells without any alterations of cellular biology; therefore this approach might be a suitable method for targeting stem cells.

  View details for DOI 10.1007/s00259-002-1110-0

  View details for Web of Science ID 000184644800016

  View details for PubMedID 12567250

• Detection and quantification of breast tumor necrosis with MR imaging: Value of the necrosis-avid contrast agent Gadophrin-3 ACADEMIC RADIOLOGY Metz, S., Daldrup-Link, H. E., Richter, T., Rath, C., Ebert, W., Settles, M., Rummeny, E. J., Link, T. M., Piert, M. 2003; 10 (5): 484-490

  Abstract

  The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis.Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings.In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis.Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.

  View details for Web of Science ID 000182566800003

  View details for PubMedID 12755535

• Macromolecular contrast agents for MR mammography: current status EUROPEAN RADIOLOGY Daldrup-Link, H. E., Brasch, R. C. 2003; 13 (2): 354-365

  Abstract

  Macromolecular contrast media (MMCM) encompass a new class of diagnostic drugs that can be applied with dynamic MRI to extract both physiologic and morphologic information in breast lesions. Kinetic analysis of dynamic MMCM-enhanced MR data in breast tumor patients provides useful estimates of tumor blood volume and microvascular permeability, typically increased in cancer. These tumor characteristics can be applied to differentiate benign from malignant lesions, to define the angiogenesis status of cancers, and to monitor tumor response to therapy. The most immediate challenge to the development of MMCM-enhanced mammography is the identification of those candidate compounds that demonstrate the requisite long intravascular distribution and have the high tolerance necessary for clinical use. Potential mammographic applications and limitations of various MMCM, defined by either experimental animal testing or clinical testing in patients, are reviewed in this article.

  View details for DOI 10.1007/s00330-002-1719-1

  View details for Web of Science ID 000181089400019

  View details for PubMedID 12599002

• Comparison between gadopentetate and feruglose (Clariscan (TM))-enhanced MR-mammography: Preliminary clinical experience Contrast Media Research Conference Daldrup-Link, H. E., Kaiser, A., Link, T. M., Settles, M., Helbich, T., Werner, M., Roberts, T. P., Rummeny, E. J. ELSEVIER SCIENCE INC. 2002: S343–S347

  View details for Web of Science ID 000177420700025

  View details for PubMedID 12188270

• Iron-oxide-enhanced MR imaging of bone marrow in patients with non-Hodgkin's lymphoma: differentiation between tumor infiltration and hypercellular bone marrow EUROPEAN RADIOLOGY Daldrup-Link, H. E., Rummeny, E. J., Ihssen, B., Kienast, J., Link, T. M. 2002; 12 (6): 1557-1566

  Abstract

  The aim of this study was to differentiate normal, hypercellular, and neoplastic bone marrow based on its MR enhancement after intravenous administration of superparamagnetic iron oxides in patients with cancer of the hematopoietic system. Eighteen patients with cancer of the hematopoietic system underwent MRI of the spine before and after infusion of ferumoxides ( n=9) and ferumoxtran ( n=9) using T1- and T2-weighted turbo spin-echo (TSE) and short tau inversion recovery sequences (STIR). In all patients diffuse or multifocal bone marrow infiltration was suspected, based on iliac crest biopsy and imaging such as conventional radiographs, MRI, and positron emission tomography. In addition, all patients had a therapy-induced normocellular ( n=7) or hypercellular ( n=11) reconversion of the normal non-neoplastic bone marrow. The MRI data were analyzed by measuring pre- and post-contrast signal intensities (SI) of hematopoietic and neoplastic marrow and by calculating the enhancement as deltaSI(%) data and the tumor-to-bone-marrow contrast as contrast-to-noise ratios (CNR). Changes in bone marrow signal intensity after iron oxide administration were more pronounced on STIR images as compared with T1- and T2-weighted TSE images. The STIR images showed a strong signal decline of normal and hypercellular marrow 45-60 min after iron oxide infusion, but no or only a minor signal decline of neoplastic bone marrow lesions; thus, deltaSI% data were significantly higher in normal and hypercellular reconverted marrow compared with neoplastic bone marrow lesions ( p<0.05). Additionally, the contrast between focal or multifocal neoplastic bone marrow infiltration and normal bone marrow, quantified by CNR data, increased significantly on post-contrast STIR images compared with precontrast images ( p<0.05). Superparamagnetic iron oxides are taken up by normal and hypercellular reconverted bone marrow, but not by neoplastic bone marrow lesions, thereby providing significantly different enhancement patterns on T2-weighted MR images; thus, superparamagnetic iron oxides are useful to differentiate normal and neoplastic bone marrow and to increase the bone marrow-to-tumor contrast.

  View details for DOI 10.1007/s00330-001-1270-5

  View details for Web of Science ID 000176197400041

  View details for PubMedID 12042968

• Atypical mycobacteriosis of the breast: MR imaging ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN Kaiser, A., Werner, M., Daldrup-Link, H. E. 2002; 174 (2): 236-237

  View details for Web of Science ID 000174029400014

  View details for PubMedID 11898088

• FDG-PET for detection of recurrences from malignant primary bone tumors: comparison with conventional imaging ANNALS OF ONCOLOGY Franzius, C., Daldrup-Link, H. E., Wagner-Bohn, A., Sciuk, J., Heindel, W. L., Jurgens, H., Schober, O. 2002; 13 (1): 157-160

  Abstract

  The aim of this study was to assess the diagnostic ability of positron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) in the detection of recurrences from malignant primary bone tumors compared with conventional imaging.In 27 patients (6 osteosarcomas, 21 Ewing's sarcomas), 41 FDG-PET examinations performed for diagnosis or exclusion of recurrent disease were evaluated. Conventional imaging techniques consisted of magnetic resonance imaging of the primary tumor site, thoracic computed tomography, and Tc-99m methylene diphosphonate bone scintigraphy. The reference methods were the histopathological analysis and/or the clinical and imaging follow-up.In 25 examinations reference methods revealed 52 sites of recurrent disease (local n = 7; distant: osseous n = 22, pulmonary n = 13, soft tissue n = 10). On an examination-based analysis FDG-PET had a sensitivity of 0.96, a specificity of 0.81 and an accuracy of 0.90. Corresponding values for conventional imaging were 1.0, 0.56 and 0.82.The sensitivity, specificity and accuracy of FDG-PET in the detection of recurrences from osseous sarcomas are high. On an examination-based analysis, FDG-PET had a not significantly lower sensitivity in comparison with conventional imaging. However, FDG-PET showed a small advantage in the detection of osseous and soft-tissue recurrences compared with conventional imaging.

  View details for DOI 10.1093/annonc/mdf012

  View details for Web of Science ID 000174060900037

  View details for PubMedID 11863097

• Whole-body MR imaging for detection of bone metastases in children and young adults: Comparison with skeletal scintigraphy and FDG PET AMERICAN JOURNAL OF ROENTGENOLOGY Daldrup-Link, H. E., Franzius, C., Link, T. M., Laukamp, D., Sciuk, J., Jurgens, H., Schober, O., Rummeny, E. J. 2001; 177 (1): 229-236

  Abstract

  The purpose of this study was to compare the diagnostic accuracy of whole-body MR imaging, skeletal scintigraphy, and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for the detection of bone metastases in children.Thirty-nine children and young adults who were 2--19 years old and who had Ewing's sarcoma, osteosarcoma, lymphoma, rhabdomyosarcoma, melanoma, and Langerhans' cell histiocytosis underwent whole-body spin-echo MR imaging, skeletal scintigraphy, and FDG PET for the initial staging of bone marrow metastases. The number and location of bone and bone marrow lesions diagnosed with each imaging modality were correlated with biopsy and clinical follow-up as the standard of reference.Twenty-one patients exhibited 51 bone metastases. Sensitivities for the detection of bone metastases were 90% for FDG PET, 82% for whole-body MR imaging, and 71% for skeletal scintigraphy; these data were significantly different (p < 0.05). False-negative lesions were different for the three imaging modalities, mainly depending on lesion location. Most false-positive lesions were diagnosed using FDG PET.Whole-body MR imaging has a higher sensitivity than skeletal scintigraphy for the detection of bone marrow metastases but a lower sensitivity than FDG PET.

  View details for Web of Science ID 000169457900045

  View details for PubMedID 11418435

• [Experimental studies of the value of SPIO for MRI of bone marrow before and after whole body irradiation]. RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin Daldrup-Link, H. E., Reinländer, C., Link, T. M., Richter, K. J., Könemann, S., Rummeny, E. J. 2001; 173 (6): 547-553

  Abstract

  Evaluation of the value of superparamagnetic iron oxides (SPIO; Endorem) for MRI-derived quantifications of the permeability of the blood-bone marrow barrier and the phagocytic activity of reticuloendothelial system (RES) bone marrow cells before and after TBI.12 New Zealand white rabbits underwent MRI of the lumbar spine and os sacrum using T1-weighted spinecho (SE) and T2-weighted Turbo-SE (TSE) sequences before and after injection of SPIO (Endorem). Four animals each were examined without irradiation, after 4 Gy total body irradiation (TBI), and after 12 Gy TBI. Changes in bone marrow signal intensities (SI) after contrast agent injection were quantified as delta SI(%) = SIpost-SIpre)/SIpre) x 100% and these data were correlated with bone marrow histopathology.Histopathology of the bone marrow revealed a radiation-induced decline of all hematopoetic cell lines. SPIO were phagocytosed by bone marrow RES cells and caused a significant bone marrow signal decline on postcontrast T2-weighted images (p < 0.05). delta SI(%) data for T2-weighted images were significantly higher for the irradiated bone marrow as compared to non-irradiated controls (p < 0.05). Dynamic T1-weighted images directly after contrast medium injection were not able to characterize the permeability of the blood-bone marrow barrier.Hematopoetic bone marrow can be labelled with SPIO. Irradiation does not impair the phagocytic activity of bone marrow RES cells. However, the bone marrow enhancement with SPIO is smaller as compared to previous results obtained by our group with USPIO.

  View details for PubMedID 11482316

• Value of SPIO for MRI of the bone marrow before and after Total Body Irradiation (TBI) - Initial investigations in an animal model. ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN Daldrup-Link, H. E., Reinlander, C., Link, T. M., Richter, K. J., Konemann, S., Rummeny, E. J. 2001; 173 (6): 547-553

  View details for Web of Science ID 000169670100012

• FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: Comparison with spiral CT ANNALS OF ONCOLOGY Franzius, C., Daldrup-Link, H. E., Sciuk, J., Rummeny, E. J., Bielack, S., Jurgens, H., Schober, O. 2001; 12 (4): 479-486

  Abstract

  The purpose was the comparison of positron emission tomography using F-18-fluorodeoxy-glucose (FDG-PET) and spiral thoracic CT to detect pulmonary metastases from malignant primary osseous tumors.In 71 patients with histologically confirmed malignant primary bone tumors (32 osteosarcomas, 39 Ewing's sarcomas) 111 FDG-PET examinations were evaluated with regard to pulmonary/pleural metastases in comparison with spiral thoracic CT. Reference methods were the clinical follow-ups for 6-64 months (median 20 months) or a histopathologic analysis.In 16 patients (23%) reference methods revealed a pulmonary/pleural metastatic disease. FDG-PET had a sensitivity of 0.50, a specificity of 0.98, and an accuracy of 0.87 on a patient based analysis. Comparable values for spiral CT were 0.75, 1.00, and 0.94. It was shown that no patient who had a true positive FDG-PET had a false negative CT scan, nor was a pulmonary metastases detected earlier by FDG-PET than by spiral CT.There seems to be a superiority of spiral CT in the detection of pulmonary metastases from malignant primary bone tumors as compared with FDG-PET. Therefore, at present a negative FDG-PET cannot be recommended to exclude lung metastases. However, as specificity of FDG-PET is high, a positive FDG-PET result can be used to confirm abnormalities seen on thoracic CT scans as metastatic.

  View details for Web of Science ID 000168326800017

  View details for PubMedID 11398879

• Carboxymethyldextran-A2-Gd-DOTA enhancement patterns in the abdomen and pelvis in an animal model EUROPEAN RADIOLOGY Daldrup-Link, H. E., Link, H. M., Moller, H. E., Wiedermann, D., Bonnemain, B., Corot, C., Rummeny, E. J. 2001; 11 (7): 1276-1284

  Abstract

  The aim of this study was to assess MR signal enhancement patterns of carboxymethyldextran (CMD)-A2-Gd-DOTA, a new macromolecular contrast agent, in the abdomen and pelvis of New Zealand white rabbits. Nine New Zealand white rabbits underwent MRI before and following injection of 0.05 mmol/kg body weight (bw) CMD-A2-Gd-DOTA (52.1 kDa), using turbo FLASH-, dynamic FLASH 60 degrees-, T1- and T2-weighted spin-echo and turbo spin-echo sequences up to 10 days p.i. Changes in blood and tissue signal intensities (deltaSI) and relaxation rates (deltaR1) were calculated. Differences between pre- and post-contrast MRI data were compared using the Scheffé test. CMD-A2-Gd-DOTA demonstrated significant blood-pool enhancement and significant tissue enhancement on T1-weighted images, whereas no significant signal changes were observed on T2-weighted images (P < 0.05). Kidney parenchyma, pelvis and bladder demonstrated a subsequent enhancement, resembling renal elimination of the majority of the contrast agent. Liver parenchyma demonstrated a slow, delayed decay of the contrast enhancement due to storage and biodegradation of larger subfractions of the contrast agent. All tissue signal intensities were back to baseline 10 days p.i. CMD-A2-Gd-DOTA is a new macromolecular contrast agent with blood-pool effect, significant signal enhancement of abdominal organs and pelvic bone marrow, partial storage in the liver and baseline tissue signal intensities by 10 days p.i.

  View details for Web of Science ID 000169752900029

  View details for PubMedID 11471624

• Quantitative gadopentetate-enhanced MRI of breast tumors: Testing of different analytic methods 6th ISMRM Scientific Meeting Helbich, T. H., Roberts, T. P., Gossmann, A., Wendland, M. F., Shames, D. M., Adachi, M., Yang, S., Huber, S., Daldrup, H., Brasch, R. C. JOHN WILEY & SONS INC. 2000: 915–24

  Abstract

  This study assessed several proposed imaging strategies and analytic methods based on gadopentetate-enhanced MRI to differentiate benign from malignant breast tumors in a blinded experimental animal study. Steady-state dynamic MRI and first-pass imaging, performed with either T(1)- or T*(2)- weighted sequences, were compared. Semiquantitative and quantitative analysis methods, based on empirical measures of the data or physiological models, were subsequently applied to the imaging datasets. Comparative measures provided pathologic distinction of benign from malignant tumors, tumor grading, and histologic determination of microvascular density. Of the eight tested methods, only one, an estimate of first-pass perfusion using T *(2)-weighted imaging, showed an almost significant (P = 0.05) difference between benign and malignant tumors and correlated almost significantly (r =.3, P = 0.06) with the tumor grade. All other tests, performed either with steady-state imaging or with T(1)-weighted first-pass imaging, failed to differentiate benign from malignant tumors. In addition, they yielded poor correlations with tumor grade and microvascular density.

  View details for Web of Science ID 000165551700013

  View details for PubMedID 11108629

• Comparison of Gadomer-17 and gadopentetate dimeglumine for differentiation of benign from malignant breast tumors with MR imaging ACADEMIC RADIOLOGY Daldrup-Link, H. E., Shames, D. M., Wendland, M., Muhler, A., Gossmann, A., Rosenau, W., Brasch, R. C. 2000; 7 (11): 934-944

  Abstract

  This study compared gadopentetate dimeglumine (molecular weight, 0.5 kD), a standard contrast medium, and Gadomer-17 (apparent molecular weight, approximately 35 kD), a new, clinically applicable, large-molecular contrast medium, with respect to their microvascular characterizations of experimentally induced breast tumors at magnetic resonance (MR) imaging.A spectrum of breast tumors, benign through highly malignant, was induced in Sprague-Dawley rats (n = 30) by intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), a potent carcinogen. All animals underwent three-dimensional spoiled gradient-recalled MR imaging, with precontrast imaging and dynamic postcontrast imaging after injection of gadopentetate dimeglumine (0.1 mmol/kg) and Gadomer-17 (0.03 mmol/kg), administered in a random order at a 24-hour interval. Several microvascular parameters were compared: the endothelial transfer coefficient (K(PS)), a measure of microvascular permeability; the fractional plasma volume (fPV), and the plasma equivalent volume. Each MR imaging parameter was correlated with histopathologic findings.With Gadomer-17, the mean values for K(PS) and fPV were significantly greater in carcinomas than in fibroadenomas (P < .004 and .04, respectively). With gadopentetate dimeglumine, the mean values for fPV and PEV were significantly greater in carcinomas (P <. 004 and .02, respectively). Because of the high variability within both fibroadenoma and carcinoma groups, however, there were no significant correlations between K(PS), fPV, or PEV and histopathologic tumor grade as indicated by the Scarff-Bloom-Richardson score, for either agent.Although the K(PS) and fPV estimates obtained from dynamic MR imaging data with Gadomer-17 enhancement offer some potential for characterizing breast tumors, none of the quantitative microvascular parameters derived with either agent were significantly correlated with histopathologic tumor grade.

  View details for Web of Science ID 000165094400005

  View details for PubMedID 11089696

• Evaluation of the accuracy of gadobenate dimeglumine-enhanced MR imaging in the detection and characterization of focal liver lesions AMERICAN JOURNAL OF ROENTGENOLOGY Pirovano, G., Vanzulli, A., Marti-Bonmati, L., Grazioli, L., Manfredi, R., Greco, A., Holzknecht, N., Daldrup-Link, H. E., Rummeny, E., Hamm, B., Arneson, V., Imperatori, L., Kirchin, M. A., Spinazzi, A. 2000; 175 (4): 1111-1120

  Abstract

  We evaluated the extent to which hepatic lesion characterization and detection is improved by using gadobenate dimeglumine for enhancement of MR images.Eighty-six patients were imaged before gadobenate dimeglumine administration, immediately after the 2 mL/sec bolus administration of a 0.05 mmol/kg dose (dynamic imaging), and at 60-120 min after the IV infusion at 10 mL/min of a further 0.05 nmol/kg dose (delayed imaging). The accuracy for lesion characterization was assessed for a total of 107 lesions. Sensitivity for lesion detection was assessed for a total of 149 lesions detected on either intra-operative sonography, iodized oil CT, CT during arterial portography, or follow-up contrast-enhanced CT as the gold standard.The accuracy in differentiating benign from malignant liver lesions increased from 75% and 82% (the findings of two observers) on unenhanced images alone, to 89% and 80% on dynamic images alone (p<0.001, p = 0.8), and to 90.7% when combining the unenhanced and dynamic image sets (p<0.001, p = 0.023). Delayed images did not further improve accuracy (90% and 91%; p = 0.002, p< 0.05). A similar trend was apparent in terms of accuracy for specific diagnosis: values ranged from 49% and 62% on unenhanced images alone, to 76% and 70% on combined unenhanced and dynamic images (p<0.001, p = 0.06), and to 75% and 70% on inclusion of delayed images (p<0.001, p = 0.12). The sensitivity for lesion detection increased from 77% and 81% on unenhanced images alone, to 87% and 85% on combined unenhanced and dynamic images (p = 0.001, p = 0.267), and to 92% and 89% when all images were considered (p<0.001, p = 0.01).Contrast-enhanced dynamic MR imaging with gadobenate dimeglumine significantly increases sensitivity and accuracy over unenhanced imaging for the characterization of focal hepatic lesions, and delayed MR imaging contributes to the improved detection of lesions.

  View details for Web of Science ID 000089490500035

  View details for PubMedID 11000175

• FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy EUROPEAN JOURNAL OF NUCLEAR MEDICINE Franzius, C., Sciuk, J., Daldrup-Link, H. E., Jurgens, H., Schober, O. 2000; 27 (9): 1305-1311

  Abstract

  The purpose of this study was to compare positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) and technetium-99m methylene diphosphonate (MDP) bone scintigraphy in the detection of osseous metastases from malignant primary osseous tumours. In 70 patients with histologically proven malignant primary bone tumours (32 osteosarcomas, 38 Ewing's sarcomas), 118 FDG-PET examinations were evaluated. FDG-PET scans were analysed with regard to osseous metastases in comparison with bone scintigraphy. The reference methods for both imaging modalities were histopathological analysis, morphological imaging [additional conventional radiography, computed tomography (CT) or magnetic resonance imaging (MRI)] and/or clinical follow-up over 6-64 months (median 20 months). In 21 examinations (18%) reference methods revealed 54 osseous metastases (49 from Ewing's sarcomas, five from osteosarcomas). FDG-PET had a sensitivity of 0.90, a specificity of 0.96 and an accuracy of 0.95 on an examination-based analysis. Comparable values for bone scintigraphy were 0.71, 0.92 and 0.88. On a lesion-based analysis the sensitivity of FDG-PET and bone scintigraphy was 0.80 and 0.72, respectively. Analysing only Ewing's sarcoma patients, the sensitivity, specificity and accuracy of FDG-PET and bone scan were 1.00, 0.96 and 0.97 and 0.68, 0.87 and 0.82, respectively (examination-based analysis). None of the five osseous metastases from osteosarcoma were detected by FDG-PET, but all of them were true-positive using bone scintigraphy. In conclusion, the sensitivity, specificity and accuracy of FDG-PET in the detection of osseous metastases from Ewing's sarcomas are superior to those of bone scintigraphy. However, in the detection of osseous metastases from osteosarcoma, FDG-PET seems to be less sensitive than bone scintigraphy.

  View details for Web of Science ID 000089201700006

  View details for PubMedID 11007511

• Focal liver lesions: Evaluation of the efficacy of gadobenate dimeglumine in MR imaging - A multicenter phase III clinical study RADIOLOGY Petersein, J., Spinazzi, A., Giovagnoni, A., Soyer, P., Terrier, F., Lencioni, R., Bartolozzi, C., Grazioli, L., Chiesa, A., Manfredi, R., Marano, P., van Meerten, E. L., Bloem, J. L., Petre, C., Marchal, G., Greco, A., McNamara, M. T., Heuck, A., Reiser, M., Laniado, M., Claussen, C., Daldrup, H. E., Rummeny, E., Kirchin, M. A., Pirovano, G., Hamm, B. 2000; 215 (3): 727-736

  Abstract

  To evaluate gadobenate dimeglumine (Gd-BOPTA) for dynamic and delayed magnetic resonance (MR) imaging of focal liver lesions.In 126 of 214 patients, MR imaging was performed before Gd-BOPTA administration, immediately after bolus administration of a 0.05- mmol/kg dose of Gd-BOPTA, and 60-120 minutes after an additional intravenously infused 0.05-mmol/kg dose. In 88 patients, imaging was performed before and 60-120 minutes after a single, intravenously infused 0.1-mmol/kg dose. T1- and T2-weighted spin-echo and T1-weighted gradient-echo images were acquired. On-site and blinded off-site reviewers prospectively evaluated all images. Intraoperative ultrasonography, computed tomography (CT) during arterial portography, and/or CT with iodized oil served as the reference methods in 110 patients.Significantly more lesions were detected on combined pre- and postcontrast images compared with on precontrast images alone (P <. 01). All reviewers reported a decreased mean size of the smallest detected lesion and improved lesion conspicuity on postcontrast images. All on-site reviewers and two off-site reviewers reported increased overall diagnostic confidence (P <.01). Additional lesion characterization information was provided on up to 109 (59%) of 184 delayed images and for up to 50 (42%) of 118 patients in whom dynamic images were assessed. Gd-BOPTA would have helped change the diagnosis in 99 (47%) of 209 cases and affected patient treatment in 408 (23%) of 209 cases.Gd-BOPTA increases liver lesion conspicuity and detectability and aids in the characterization of lesions.

  View details for Web of Science ID 000087247000018

  View details for PubMedID 10831691

• CT of metal implants: Reduction of artifacts using an extended CT scale technique JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Link, T. M., Berning, W., Scherf, S., Joosten, U., Joist, A., Engelke, K., Daldrup-Link, H. E. 2000; 24 (1): 165-172

  Abstract

  The purpose of this work was to use an extended CT scale technique (ECTS) to reduce artifacts due to metal implants and to optimize CT imaging parameters for metal implants using an experimental model.Osteotomies were performed in 20 porcine femur specimens. One hundred cobalt-base screws and 24 steel plates were used for osteosynthesis in these specimens. Artificial lesions were produced in 50 screws, such as osteolysis near the screws (mimicking lysis due to infection, tumor, or loosening), displacement of the screws, as well as fractures of the screws. All specimens were examined using eight different CT protocols: four conventional (CCT) and four spiral (SCT) CT protocols with different milliampere-second values (130 and 480 mAs for CCT, 130 and 300 mAs for SCT), kilovolt potentials (120 and 140 kVp), and slice thicknesses (2 and 5 mm). The images were analyzed by three observers using a standard window (maximum window width 4,000 HU) and ECTS (maximum window width 40,000 HU). Receiver operating characteristic analysis was performed, and image quality was assessed according to a five level scale.Metal artifacts were significantly reduced using ECTS (p < 0.05). The highest diagnostic performance was obtained using ECTS with the thinnest slice thickness. Metal artifacts were more pronounced using SCT. In this experimental model, exposure dose and kilovolt potential had no significant impact on diagnostic performance (p > 0.05).ECTS improved imaging of metal implants. In this study, no significant effects of exposure dose and kilovolt potential were noted. Metal artifacts were more prominent using SCT than using CCT.

  View details for Web of Science ID 000084876600029

  View details for PubMedID 10667677

• Assessing permeability alterations of the blood-bone marrow barrier due to total body irradiation: in vivo quantification with contrast enhanced magnetic resonance imaging BONE MARROW TRANSPLANTATION Daldrup-Link, H. E., Link, T. M., Rummeny, E. J., August, C., Konemann, S., Jurgens, H., Heindel, W. 2000; 25 (1): 71-78

  Abstract

  Our aim was to quantify irradiation-induced permeability alterations of the blood-bone marrow barrier (BMB) with dynamic contrast enhanced magnetic resonance imaging (MRI). The standard small molecular contrast agent, gadoterate meglumine, and a new macromolecular contrast agent, carboxymethyldextran-Gd-DOTA (CMD-Gd-DOTA), were compared. Twenty New Zealand white rabbits underwent MRI of the bone marrow before and 1-2 days after total body irradiation (TBI). Dynamic, repetitive T1-weighted MRI was performed before and after injection of either 0.05 mmol/kg BW CMD-Gd-DOTA (n = 10) or 0.5 mmol/kg BW gadoterate (n = 10). Bone marrow contrast enhancement was quantified as delta signal intensity: DeltaSI = |(SIpost - SIpre) / SIpre| * 100%. All MRI data were compared with the histopathologic BMB ultrastructure. Dynamic bone marrow DeltaSI data steadily increased after CMD-Gd-DOTA injection, while blood DeltaSI data slightly decreased. This bone marrow contrast enhancement, indicative of contrast agent extravasation, was significantly higher and prolonged in the irradiated group as compared to non-irradiated controls (P < 0.05) and corresponded to irradiation-induced alterations of the BMB ultrastructure seen on electron microscopy. By contrast, DeltaSI data of non-irradiated and irradiated marrow were not significantly different following gadoterate injection (P > 0.05). We conclude that irradiation-induced alterations in BMB permeability could be reliably assessed with dynamic MRI, using the new macromolecular contrast agent CMD-Gd-DOTA. Bone Marrow Transplantation (2000) 25, 71-78.

  View details for Web of Science ID 000085213100013

  View details for PubMedID 10654018

• Monitoring radiation-induced changes in bone marrow histopathology with ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI JOURNAL OF MAGNETIC RESONANCE IMAGING Daldrup, H. E., Link, T. M., Blasius, S., Strozyk, A., Konemann, S., Jurgens, H., Rummeny, E. J. 1999; 9 (5): 643-652

  Abstract

  The purpose of this study was to monitor radiation-induced alterations of the blood-bone marrow barrier (BMB) and the reticuloendothelial system (RES) with AMI-227-enhanced magnetic resonance imaging (MRI). Twenty New Zealand white rabbits (n = 10 following total body irradiation and n = 10 controls) underwent AMI-227-enhanced MRI. Pulse sequences included dynamic fast low-angle shot (FLASH; TR/TE 50/4 msec, flip angle 60 degrees) MRI and static T1- and T2-weighted spin-echo (SE) and turbo-SE sequences of the lumbar spine and sacrum. Bone marrow enhancement was quantified as delta signal intensity (SI) (%) =|[(SIpost - SIpre)/SIpre] x 100%| and compared with histopathology, including iron stains and electron microscopy. Dynamic bone marrow deltaSI (%) data steadily increased up to 10-15 minutes after AMI-227 administration, while blood deltaSI (%) data stayed nearly constant, histologically corresponding to iron oxide leakage into the bone marrow interstitium. This bone marrow contrast enhancement increased significantly following irradiation, corresponding to alterations of the endothelial lining of the bone marrow sinusoids. Late postcontrast images exhibited a significant positive T1 enhancement and negative T2 enhancement of the normal bone marrow, which further increased with irradiation due to increased RES activity. Irradiation-induced changes in bone marrow physiology could be reliably assessed with AMI-227-enhanced MRI.

  View details for Web of Science ID 000083418000005

  View details for PubMedID 10331759

• Tumor flood volume assays using contrast-enhanced magnetic resonance imaging: Regional heterogeneity and postmortem artifacts JOURNAL OF MAGNETIC RESONANCE IMAGING Okuhata, Y., Brasch, R. C., Pham, C. D., Daldrup, H., Wendland, M. F., Shames, D. M., Roberts, T. P. 1999; 9 (5): 685-690

  Abstract

  Tumor blood volume (BV), subject to both morphologic and physiologic influences, can be measured using contrast-enhanced magnetic resonance imaging (MRI). The aims of this study were to determine whether MRI enhanced with a macromolecular contrast medium (MMCM) could resolve differences in BV between different tumor types, between different regions within tumors, and within the same tumor in life and after death. Tumor BV estimates were based on the MRI signal intensity responses in the tumors and in reference venous blood following enhancement with a blood pool MMCM using two mammary adenocarcinoma models. Estimates of BV were made before and immediately following death. An in vitro measurement of tumor gadolinium concentration following death was correlated with MRI enhancement. Statistically significant differences (P < 0.05) were observed in MRI-estimated tumor BV between tumor subtypes, between in vivo and postmortem measurements, and between the tumor periphery and tumor centers. MRI assays enhanced with a macromolecular contrast agent can resolve blood volume differences between tumor types, between regions within the same tumor, and between vital and postmortem states.

  View details for Web of Science ID 000083418000010

  View details for PubMedID 10331764

• Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: Comparison of macromolecular and small-molecular contrast media 40th Annual Meeting of the Society-for-Pediatric-Radiology Daldrup, H., Shames, D. M., Wendland, M., Okuhata, Y., Link, T. M., Rosenau, W., Lu, Y., Brasch, R. C. AMER ROENTGEN RAY SOC. 1998: 941–49

  Abstract

  The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic MR imaging were correlated with histopathologic grade in mammary soft-tissue tumors.A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N-ethyl-N-nitrosourea, a potent carcinogen. Dynamic contrast-enhanced MR imaging was performed using a small-molecular contrast medium (gadopentetate, molecular weight = 0.5 kDa) and a macromolecular contrast medium (albumin-(Gd-DTPA)30, molecular weight = 92 kDa) at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (K(PS)), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bidirectional kinetic model. MR imaging microvascular characteristics were correlated with histopathologic tumor grade.Tumor permeability to macromolecular contrast medium, characterized by K(PS), showed a highly positive correlation with tumor grade (r2 = .76, p < 10(-10)). K(PS) values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r2 = .25, p < .003). No correlation between K(PS) or fPV values and tumor grade was found using gadopentetate (r2 = .01, p > .95 and r2 = .03, p > .15, respectively).Quantitative tumor microvascular permeability assays generated with macromolecular MR imaging contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

  View details for Web of Science ID 000076117300007

  View details for PubMedID 9762973

• Quantification of the extraction fraction for gadopentetate across breast cancer capillaries MAGNETIC RESONANCE IN MEDICINE Daldrup, H. E., Shames, D. M., Husseini, W., Wendland, M. F., Okuhata, Y., Brasch, R. C. 1998; 40 (4): 537-543

  Abstract

  To quantify the extraction fraction, E, for gadopentetate across tumor capillaries, R3230 adenocarcinomas were implanted in the mammary fat pads of seven rats. The value of E was determined by using a two-compartment tissue model in which the endothelial transfer coefficient, K(PS) (ml x min(-1) x cc(-1) of tissue), was estimated from the model fitted to changes in R1 relaxation time (deltaR1; s(-1)) measured by dynamic three-dimensional spoiled gradient recalled magnetic resonance imaging after injection of 0.1 mmol x kg(-1) of gadopentetate dimeglumine. The plasma flow rate through the tumor capillaries, Fp, (ml x min(-1) x g(-1) of tissue), was independently measured with fluorescent microspheres. E could be calculated by the relationship, E = K(PS)/Fp. The mean E for gadopentetate in the R3230 tumor was 0.197 +/- 0.118 with a range of 0.123-0.454. The relatively small mean value of E for gadopentetate allows a fair approximation of the permeability surface area product by K(PS) in this R3230 tumor model.

  View details for Web of Science ID 000076080900005

  View details for PubMedID 9771570

• MR imaging of thoracic tumors in pediatric patients AMERICAN JOURNAL OF ROENTGENOLOGY Daldrup, H. E., Link, T. M., Wortler, K., Reimer, P., Rummeny, E. J. 1998; 170 (6): 1639-1644

  View details for Web of Science ID 000073769500045

  View details for PubMedID 9609188

• Macromolecular contrast media-enhanced MRI estimates of microvascular permeability correlate with histopathologic tumor grade Symposium on Contrast Media Research Brasch, R. C., Daldrup, H., Shames, D., Wendland, M., Okuhata, Y., Rosenau, W. ELSEVIER SCIENCE INC. 1998: S2–S5

  View details for Web of Science ID 000073207400002

  View details for PubMedID 9561030

• Correlation of dynamic contrast-enhanced magnetic resonance imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media PEDIATRIC RADIOLOGY Daldrup, H., Shames, D. M., Wendland, M., Okuhata, Y., Link, T. M., Rosenau, W., Lu, Y., Brasch, R. C. 1998; 28 (2): 67-78

  Abstract

  The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic magnetic resonance imaging (MRI) were correlated with histopathologic grade in mammary soft tissue tumors.A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N -ethyl-N -nitrosourea (ENU), a potent carcinogen. Dynamic contrast-enhanced MRI was performed using a small-molecular contrast medium [gadopentetate, MW = 0.5 kDa] and a macromolecular contrast medium [albumin-(Gd-DTPA)30, MW = 92 kDa] at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (KPS), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bi-directional kinetic model. MRI microvascular characteristics were correlated with histopathologic tumor grade.Tumor permeability to macromolecular contrast medium, characterized by KPS, showed a highly positive correlation with tumor grade (r 2 = 0.76, P < 10(-10)). KPS values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r 2 = 0.25, P < 0.003). No correlation between KPS or fPV values and tumor grade was found using gadopentetate (r 2 = 0.01, P > 0.95 and r2 = 0.03, P > 0.15, respectively).Quantitative tumor microvascular permeability assays generated with macromolecular MRI contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

  View details for Web of Science ID 000072138600001

  View details for PubMedID 9472047

• High resolution MRI of small joints: Impact of spatial resolution on diagnostic performance and SNR MAGNETIC RESONANCE IMAGING Link, T. M., Majumdar, S., Peterfy, C., Daldrup, H. E., Uffmann, M., Dowling, C., Steinbach, L., Genant, H. K. 1998; 16 (2): 147-155

  Abstract

  This study focuses on the spatial resolution required for cartilage imaging. The purposes of this study were (I) to analyze the diagnostic performance in diagnosing artificially produced cartilage lesions in a small joint model using an optimized fat saturated three-dimensional gradient-echo sequence, (II) to relate the lesion size and depth as diagnosed in the magnetic resonance images with the corresponding pathologic findings and (III) to assess signal-to-noise (SNR) ratios for each of the protocols. Twenty-five artificial cartilage lesions were created in the knee joints of 10 rabbits. These specimens and seven specimens without lesions were imaged at 1.5 T using a three-dimensional gradient-echo sequence with varying slice thickness, field of view and matrix. A total of 404 corresponding images were selected, 50% with and 50% without cartilage lesions. Six radiologists scored all images according to five levels of confidence and receiver operating characteristic (ROC) analysis was performed. Lesion size and depth were compared to the corresponding pathological specimen sections. Additionally SNR ratios were calculated. ROC analysis of pooled data from all readers showed the highest area under the ROC curve for the sequence with the highest spatial resolution, while the diagnostic performance was significantly lower in the other sequences (p <0.01). Assessment of the lesion size and depth was correct in 45% and 40% respectively with the highest resolution and in 29% and 23% with the lowest resolution. SNR ratios decreased with increasing spatial resolution. In conclusion this study shows that increasing spatial resolution improves diagnostic performance in cartilage lesions, though SNR decreases substantially. Assessment of correct lesion size and depth still is limited.

  View details for Web of Science ID 000072063800006

  View details for PubMedID 9508271

• [Macromolecular contrast media for MR mammography. A new approach to characterizing breast tumors]. Der Radiologe Daldrup, H. E., Roberts, T. P., Mühler, A., Gossmann, A., Roberts, H. C., Wendland, M., Rosenau, W., Brasch, R. C. 1997; 37 (9): 733-740

  Abstract

  The value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of "blood-pool"-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed.

  View details for PubMedID 9424619

• Enhancement characteristics of liver metastases, hepatocellular carcinomas, and hemangiomas with Gd-EOB-DTPA: Preliminary results with dynamic MR imaging EUROPEAN RADIOLOGY Reimer, P., Rummeny, E. J., Daldrup, H. E., Hesse, T., Balzer, T., Tombach, B., Peters, P. E. 1997; 7 (2): 275-280

  Abstract

  Our objective was to study Gd-EOB-DTPA for the characterization of focal liver lesions by means of dynamic MR imaging. A double-blind and randomized dose-ranging phase-2 clinical trial was performed in 31 patients (liver metastases n = 23, hepatocellular carcinoma n = 4, and hemangioma n = 4) at a field strength of 1.0 Tesla. Gd-EOB-DTPA (Schering AG, Berlin, Germany) was administered as an IV bolus (12.5, 25, or 50 micromol/kg body weight) with dynamic T1-weighted MRI during the distribution and cellular uptake of the contrast agent at multiple time points up to 45 min post contrast. Dynamic changes in tumor signal intensity, tumor-liver contrast, enhancement patterns, side effects, and adverse events were evaluated. Monitoring of vital signs revealed no significant changes during bolus injection of Gd-EOB-DTPA. Liver metastases demonstrated an inhomogeneous uptake of Gd-EOB-DTPA during the distribution phase with a washout effect on delayed images > 3 min and highest tumor-liver contrast 20 and 45 min post contrast. Hepatocellular carcinomas showed prolonged enhancement as compared with metastases and hemangiomas. Hemangiomas exhibited an early peripheral-nodular enhancement with subsequent partial or complete filling, persisting enhancement < 10 min following injection of Gd-EOB-DTPA, and delayed washout as compared with liver metastases. Initial clinical experience suggests that Gd-EOB-DTPA as a bolus injectable hepatobiliary MR contrast agent may offer useful features for the characterization of focal liver lesions.

  View details for Web of Science ID A1997WN94400023

  View details for PubMedID 9038130

• Evaluation of myelination and myelination disorders with turbo inversion recovery magnetic resonance imaging EUROPEAN RADIOLOGY Daldrup, H. E., Schuierer, G., Link, T. M., Moeller, H., Bick, U., Kurlemann, G., Peters, P. E. 1997; 7 (9): 1478-1484

  Abstract

  The aim of our work was to determine the efficacy of turbo inversion recovery spin echo (TIRSE) pulse sequences in differentiating patients with normal and abnormal myelination. Twenty neurological normal children (aged 5 months to 12 years) as well as 65 children presenting clinically with neurologic developmental deficits (aged 2 months to 10 years) were examined using TIRSE, T1-weighted SE, and T2-weighted turbo SE pulse sequences. Contrast-to-noise-ratio (CNR) between myelinated white and gray matter was compared for the different pulse sequences. In addition, two readers analyzed all images qualitatively by consensus. The CNR values were significantly higher on TIRSE images as compared with conventional images (p < 0. 05). Forty-two neurologically abnormal patients displayed a normal myelination on all sequences, whereas 23 showed an abnormal myelination. The TIRSE sequence provided a sensitive and specific depiction of an abnormal myelination in all of these patients. The TIRSE sequence provided additional information to conventional pulse sequences in determining myelination disorders in children, especially in children older than 2 years.

  View details for Web of Science ID A1997YK47800018

  View details for PubMedID 9369518

• [The value of 3-phase spiral CT and magnetic resonance tomography in preoperative diagnosis of pancreatic carcinoma]. Der Radiologe Lentschig, M. G., Reimer, P., Rummeny, E., Grenzheuser, C., Daldrup, H. E., Berns, T., Dinse, P., Sulkowski, U., Peters, P. E. 1996; 36 (5): 406-412

  Abstract

  The purpose of this study was to assess the role of spiral computed tomography (SCT) and magnetic resonance imaging (MRI) in the preoperative work-up of patients with pancreatic carcinoma, regarding local resectability and vascular involvement.A total of 28 patients (19 men and 9 women; mean age 58 years) with known or highly suspected carcinoma of the pancreas were included in this study. All patients prospectively underwent MRI ( +/- gadolinium-DTPA ) and SCT (3-phase examination) as preoperative diagnostic imaging studies, and laparotomy was carried out within 7 days, irrespective of the MRI or SCT findings. SCT and MR studies were reviewed independently by two radiologists, without knowing the results of the surgical exploration. Standardized image analysis was correlated with findings at laparatomy.Laparotomy identified 10 patients to be suitable for surgical resection and 18 pancreatic carcinomas to be unresectable. In 17 of 18 non-resectable carcinomas MRI and SCT were able to obtain correct information about unresectability (sensitivity 94%), in 7 (MRI), resp. 8 (SCT) carcinomas were correctly considered to be resectable (sensitivity 70% of MRI and 80% for SCT). The presence of vascular involvement was depicted by SCT with a sensitivity of 82-100% and 62-100% by MRI. The specificity varied between 85-100% for SCT and 77-100% for MRI.Both MRI and SCT are good techniques for the preoperative work-up of pancreatic carcinomas in order to obtain a correct assessment of local resectability.

  View details for PubMedID 8778925

• Phase II clinical evaluation of Gd-EOB-DTPA: Dose, safety aspects, and pulse sequence RADIOLOGY Reimer, P., Rummeny, E. J., Shamsi, K., Balzer, T., Daldrup, H. E., Tombach, B., Hesse, T., Berns, T., Peters, P. E. 1996; 199 (1): 177-183

  Abstract

  To investigate the efficacy of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) in the detection of focal liver lesions with respect to dose, side effects, and pulse sequence.A randomized double-blinded trial was performed in 33 patients with focal solid liver lesions. A bolus of Gd-EOB-DTPA, a liver-specific contrast agent, was intravenously administered at three different doses (12.5, 25, and 50 mumol per kilogram of body weight). Magnetic resonance imaging with different T1-weighted techniques was performed 20 and 45 minutes after administration of Gd-EOB-DTPA. Changes in liver signal intensity, lesion-liver contrast-to-noise ration (C/N), detectable liver lesions, side effects, and adverse events were evaluated.Gd-EOB-DTPA significantly (P < .05) increased liver signal intensity and lesion-liver C/N within the dose range tested. Lesion detection was improved 20 and 45 minutes after administration of Gd-EOB-DTPA. A dose of 12.5 mumol was sufficient for the detection of focal liver lesions, and the breath-hold, T1-weighted, fast low-angle shot pulse sequence was the most useful. No significant changes in vital signs, clinical laboratory test results, and urinalysis were observed.Gd-EOB-DTPA is an efficient, diagnostically useful, and safe contrast agent.

  View details for Web of Science ID A1996UB58400030

  View details for PubMedID 8633143

• [Primary non-Hodgkin's lymphoma of the skull in an 11-year-old girl. Follow-up and review of the literature]. Der Radiologe Daldrup, H. E., Reimer, P., Wolf, K. J., Peters, P. E. 1996; 36 (4): 354-359

  Abstract

  The authors present a rare case of solitary non-Hodgkin lymphoma (NHL) in the skull of an 11-year-old girl. The clinical, radiological and histological findings as well as a review of the literature are included in this report. The morphological features of intra- and extracerebral tumor masses and the change in tumor extension due to chemotherapy and radiation therapy were evaluated with magnetic resonance imaging. Although rare, NHL should be considered in the differential diagnosis of skull tumors in children.

  View details for PubMedID 8677328

• [Use of gadoteridol in MR diagnosis of rheumatoid changes in the joints]. Der Radiologe Link, T. M., Bongartz, G. M., Böger, K., Daldrup, H., Schmitz-Linneweber, B., Peters, P. E. 1996; 36 (2): 141-147

  Abstract

  To investigate the diagnostic and clinical usefulness of a new non-ionic, hydrophilic gadolinium (III) chelate [Gd(HP-DO3A), gadoteridol, ProHance] and to compare it with Gd-DTPA (gadopentetate dimeglumine, Magnevist).In a Phase III clinical trial, 20 patients with rheumatic joint disease were examined before and after intravenous administration of gadoteridol in two different doses (0.1 and 0.3 mmol/kg bodyweight). Magnetic resonance imaging (MRI) was performed at 1.5 T with T1-weighted FLASH and T2-weighted spin echo sequences. Fourteen patients were examined with gadopentetate dimeglumine for comparison. Dynamic changes of signal intensity in the joints and muscle tissue were determined quantitatively.No significant changes in cardiovascular data and no adverse effects occurred after injection of gadoteridol. The 0.3 mmol/kg dose showed no advantage in diagnostic contrast over the 0.1 mmol/kg dose. No significant differences (p > 0.01) were noted between gadoteridol and gadopentetate dimeglumine in patients with early rheumatoid arthritis.Gadoteridol proved useful in the detection of early rheumatoid arthritis. No significant differences were observed between the two gadoteridol doses. There were no diagnostically relevant differences between gadoteridol and gadopentetate dimeglumine.

  View details for PubMedID 8867431

• [New MR contrast media in liver diagnosis. Initial clinical results with hepatobiliary Eovist (gadolinium-EOB-DTPA) and RES-specific Resovist (SH U 555 A)]. Der Radiologe Reimer, P., Tombach, B., Daldrup, H., Hesse, T., Sander, G., Balzer, T., Shamsi, K., Berns, T., Rummeny, E. J., Peters, P. E. 1996; 36 (2): 124-133

  Abstract

  The purpose of this work is to describe our initial clinical experience (in 66 patients) with Resovist and Eovist, two new liver-specific MR contrast agents. We focus our report on safety aspects, dose finding, and optimization and technical parameters. Both contrast agents were well tolerated and improved the detectability of focal liver lesions. With Resovist, postcontrast MRI may be started as early as 10 min following injection. The dose of 8 mumol Fe/kg bodyweight was sufficient to achieve diagnostic tumor-liver contrast levels. Since Eovist can also be administered as a bolus, dynamic enhancement patterns may be studied for tumor characterization as well. Breath-hold T1-weighted FLASH images were superior to other T1-weighted techniques with and without fat saturation.

  View details for PubMedID 8867429

• [High dosage Gd-DPTA-BMA (Gadodiamid) administration in diagnosis and therapeutic monitoring of malignant bone tumors]. Der Radiologe Häussler, M. D., Rummeny, E. J., Raufhake, C., Blasius, S., Lindner, N., Daldrup, H. E., Reimer, P., Peters, P. E. 1996; 36 (2): 148-152

  Abstract

  To evaluate the efficacy of high-dose Gd-DTPA-BMA (gadodiamide, Omniscan) as a contrast for magnetic resonance imaging of malignant bone tumors and the use of high-dose dynamic studies for predicting the response to pre-operative chemotherapy.Examinations were performed in 22 patients with suspected malignant bone tumor on a 1.5 T system. In 8 cases a follow-up examination was done after preoperative chemotherapy. Static studies included Pd- and T2-weighted spin-echo sequences as well as T1-weighted spin-echo sequences, obtained pre- and post-contrast. Dynamic studies were performed using a FLASH 2D-gradient-echo sequence (TR 40 ms/TE 10 ms, 90 degrees flip angle) every 20 s after intravenous bolus injection of Gd-DTPA-BMA (0.3 mmol/kg body weight). MR images were evaluated qualitatively by visual assessment of conspicuity size, extraosseous delineation and structure of the lesion and quantitatively by measurement of the signal intensities and calculation of the relative increase in signal intensity.Qualitative image analysis showed best demonstration of the lesions on contrast-enhanced T1-weighted images. Comparison of T1-weighted pre- and postcontrast spin-echo sequences revealed significantly better assessment of tumor structure after administration of contrast media. After preoperative chemotherapy, all responders showed a markedly stronger reduction in relative increase in signal intensity in dynamic studies compared to nonresponders.Gd-DTPA-BMA is effective for magnetic resonance imaging of musculoskeletal lesions and improves assessment of the tumor structure. Dynamic studies may help to predict the response to preoperative chemotherapy.

  View details for PubMedID 8867432

• DETECTION OF LIVER-TUMORS RADIOLOGE Rummeny, E. J., Reimer, P., Daldrup, H., Peters, P. E. 1995; 35 (11): S252-S258

  Abstract

  Accurate detection of liver metastases in patients with known primary tumors is often essential for therapeutic decision making. Compared to conventional contrast media-enhanced CT unenhanced MRI seems to be slightly superior for the detection of small focal liver lesions. However, intraoperative US and CTAP show higher sensitivities for lesion detection but use of these techniques is limited because of their invasive character. The new superparamagnetic MR contrast medium ENDOREM improves the number of liver lesions detected significantly as compared to unenhanced MRI. Furthermore, as shown recently, ENDOREM-enhanced MRI may be as sensitive as CTAP. Thus, ENDOREM is useful for preoperative staging of liver tumors due to improvement in lesion detection and delineation of the hepatic vascular system.

  View details for Web of Science ID A1995TH49100004

  View details for PubMedID 8588031

• [The regression of a hepatocellular adenoma after the withdrawal of hormonal contraception]. RöFo : Fortschritte auf dem Gebiete der Röntgenstrahlen und der Nuklearmedizin Daldrup, H. E., Reimer, P., Rummeny, E. J., Fischer, H., Böcker, W., Peters, P. E. 1995; 163 (5): 449-451

  View details for PubMedID 8527762

• [New super-paramagnetic iron particles for MRI. Phase II study of malignant liver tumors]. Der Radiologe Daldrup, H. E., Reimer, P., Rummeny, E. J., Tombach, B., Berns, T., Balzer, T., SCHIMPFKY, C., Peters, P. E. 1995; 35 (8): 486-493

  Abstract

  The clinical tolerability and diagnostic value of Resovist as a new superparamagnetic iron oxide contrast medium was studied in 30 patients with malignant focal liver lesions (28 metastases, 2 HCC) within a phase II multicenter study. Magnetic resonance imaging (MRI) was performed at 1.0 Tesla with T1-weighted FLASH- and T2-weighted spin echo sequences before and following intravenous injection of Resovist at three different dose groups (4, 8 and 16 mumol Fe/kg). Liver signal intensity was significantly reduced on post-contrast images, while malignant focal liver lesions showed no signal changes. Resovist improved tumor liver contrast and lesion-conspicuity, especially for lesions smaller than 1 cm. The dose of 8 mumol Fe/kg was sufficient to achieve diagnostic tumor-liver contrast. Compared to images directly after injection, the number of detected lesions did not improve until 70 min later. There were no significant changes in vital signs (heart rate, blood pressure) or laboratory values until 72 h post-injection.

  View details for PubMedID 7568792

• CLINICAL-RESULTS WITH RESOVIST - A PHASE-2 CLINICAL-TRIAL RADIOLOGY Reimer, P., Rummeny, E. J., Daldrup, H. E., Balzer, T., Tombach, B., Berns, T., Peters, P. E. 1995; 195 (2): 489-496

  Abstract

  To investigate the superparamagnetic iron oxide (Resovist) designed for contrast material-enhanced magnetic resonance imaging of the liver.A phase 2 trial was performed in 33 patients with no more than five known focal solid liver lesions. Resovist was administered intravenously at doses of 4, 8, and 16 mumol of iron per kilogram of body weight. Postcontrast 1.0-T imaging was started 30 minutes after injection.Resovist significantly (P < or = .05) decreased liver signal intensity and increased lesion-to-liver contrast-to-noise ratio (C/N) and the number of detectable liver lesions: fast spin-echo (SE) (echo time, 90 msec) precontrast C/N, 11.7 +/- 7.9 [standard deviation]; postcontrast [8-mumol Fe/Kg] C/N, 29.2 +/- 14.2). The dose of 8 mumol Fe/kg was sufficient for the detection of focal liver lesions, and T2-weighted fast SE with an echo time of 90 msec was the overall best pulse sequence.Resovist is a safe contrast agent, and a dose of 8 mumol Fe/kg is sufficient to enhance detection of focal liver lesions at T2-weighted fast SE MR imaging.

  View details for Web of Science ID A1995QU71700034

  View details for PubMedID 7724772