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. Jun, 2002  |  Pubmed ID: 12042968

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.

Comparison Between Gadopentetate and Feruglose (Clariscan)-enhanced MR-mammography: Preliminary Clinical Experience

Academic Radiology. Aug, 2002  |  Pubmed ID: 12188270

Highly Efficient Paramagnetic Labelling of Embryonic and Neuronal Stem Cells

European Journal of Nuclear Medicine and Molecular Imaging. Jul, 2003  |  Pubmed ID: 12567250

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.

Macromolecular Contrast Agents for MR Mammography: Current Status

European Radiology. Feb, 2003  |  Pubmed ID: 12599002

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.

Targeting of Hematopoietic Progenitor Cells with MR Contrast Agents

Radiology. Sep, 2003  |  Pubmed ID: 12881578

To label human hematopoietic progenitor cells with various magnetic resonance (MR) imaging contrast agents and to obtain 1.5-T MR images of them.

Quantification of Breast Tumor Microvascular Permeability with Feruglose-enhanced MR Imaging: Initial Phase II Multicenter Trial

Radiology. Dec, 2003  |  Pubmed ID: 14576446

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.

Macromolecular Contrast Medium (feruglose) Versus Small Molecular Contrast Medium (gadopentetate) Enhanced Magnetic Resonance Imaging: Differentiation of Benign and Malignant Breast Lesions

Academic Radiology. Nov, 2003  |  Pubmed ID: 14626298

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.

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. Sep, 2004  |  Pubmed ID: 15138719

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.

Capacity of Human Monocytes to Phagocytose Approved Iron Oxide MR Contrast Agents in Vitro

European Radiology. Oct, 2004  |  Pubmed ID: 15249981

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.

Decrease in Tumor Apparent Permeability-surface Area Product to a MRI Macromolecular Contrast Medium Following Angiogenesis Inhibition with Correlations to Cytotoxic Drug Accumulation

Microcirculation (New York, N.Y. : 1994). Jul-Aug, 2004  |  Pubmed ID: 15280064

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.

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. Jan, 2005  |  Pubmed ID: 15616814

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.

Migration of Iron Oxide-labeled Human Hematopoietic Progenitor Cells in a Mouse Model: in Vivo Monitoring with 1.5-T MR Imaging Equipment

Radiology. Jan, 2005  |  Pubmed ID: 15618382

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.

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. Apr, 2005  |  Pubmed ID: 15831425

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.

Ultrasmall Superparamagnetic Iron-oxide-enhanced MR Imaging of Normal Bone Marrow in Rodents: Original Research Original Research

Academic Radiology. Sep, 2005  |  Pubmed ID: 16099684

The objective is to compare three different ultrasmall superparamagnetic iron oxides (USPIOs) for magnetic resonance (MR) imaging of normal bone marrow in rodents.

Mixture Model Approach to Tumor Classification Based on Pharmacokinetic Measures of Tumor Permeability

Journal of Magnetic Resonance Imaging : JMRI. Oct, 2005  |  Pubmed ID: 16161077

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.

Ferumoxtran-10-enhanced MR Imaging of the Bone Marrow Before and After Conditioning Therapy in Patients with Non-Hodgkin Lymphomas

European Radiology. Mar, 2006  |  Pubmed ID: 16284770

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).

T1 and T2 Relaxivity of Intracellular and Extracellular USPIO at 1.5T and 3T Clinical MR Scanning

European Radiology. Mar, 2006  |  Pubmed ID: 16308692

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.

Ultrasmall Supraparamagnetic Iron Oxide-enhanced Magnetic Resonance Imaging of Antigen-induced Arthritis: a Comparative Study Between SHU 555 C, Ferumoxtran-10, and Ferumoxytol

Investigative Radiology. Jan, 2006  |  Pubmed ID: 16355039

We sought to compare the ability of 3 ultrasmall superparamagnetic iron oxides (USPIOs) to detect and characterize antigen-induced arthritis with MR imaging.

MRI of Arthritis: Comparison of Ultrasmall Superparamagnetic Iron Oxide Vs. Gd-DTPA

Journal of Magnetic Resonance Imaging : JMRI. May, 2006  |  Pubmed ID: 16557494

To compare the ability of the ultrasmall superparamagnetic iron oxide (USPIO) SHU555C vs. gadopentetate dimeglumine (Gd-DTPA) to detect antigen-induced monoarthritis with MRI.

Optical Imaging of Experimental Arthritis Using Allogeneic Leukocytes Labeled with a Near-infrared Fluorescent Probe

European Journal of Nuclear Medicine and Molecular Imaging. Sep, 2006  |  Pubmed ID: 16770602

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.

Imaging of Tumor Angiogenesis: Current Approaches and Future Prospects

Current Pharmaceutical Design. 2006  |  Pubmed ID: 16842165

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.

MR Imaging of Therapy-induced Changes of Bone Marrow

European Radiology. Mar, 2007  |  Pubmed ID: 17021706

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.

Cell Labeling with the Positive MR Contrast Agent Gadofluorine M

European Radiology. May, 2007  |  Pubmed ID: 17206428

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.

MR Imaging of Antigen-induced Arthritis with a New, Folate Receptor-targeted Contrast Agent

Contrast Media & Molecular Imaging. Mar-Apr, 2007  |  Pubmed ID: 17385788

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.

Imaging Characteristics of DHOG, a Hepatobiliary Contrast Agent for Preclinical MicroCT in Mice

Academic Radiology. Mar, 2008  |  Pubmed ID: 18280932

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.

Receptor Imaging of Pediatric Tumors: Clinical Practice and New Developments

Pediatric Radiology. Nov, 2008  |  Pubmed ID: 18483730

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.

Cell Tracking with Optical Imaging

European Radiology. Oct, 2008  |  Pubmed ID: 18506449

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.

Tracking of [18F]FDG-labeled Natural Killer Cells to HER2/neu-positive Tumors

Nuclear Medicine and Biology. Jul, 2008  |  Pubmed ID: 18589302

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.

Detection of Postoperative Granulation Tissue with an ICG-enhanced Integrated OI-/X-ray System

Journal of Translational Medicine. 2008  |  Pubmed ID: 19038047

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).

Phase I Trial of Oral Irinotecan and Temozolomide for Children with Relapsed High-risk Neuroblastoma: a New Approach to Neuroblastoma Therapy Consortium Study

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2009  |  Pubmed ID: 19171709

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.

Optical Imaging of Cellular Immunotherapy Against Prostate Cancer

Molecular Imaging. Jan-Feb, 2009  |  Pubmed ID: 19344572

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.

New Perspectives on Bone Marrow Contrast Agents and Molecular Imaging

Seminars in Musculoskeletal Radiology. Jun, 2009  |  Pubmed ID: 19455477

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.

MR Imaging of Pediatric Arthritis

Magnetic Resonance Imaging Clinics of North America. Aug, 2009  |  Pubmed ID: 19524196

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.

The Influence of Ferucarbotran on the Chondrogenesis of Human Mesenchymal Stem Cells

Contrast Media & Molecular Imaging. Jul-Aug, 2009  |  Pubmed ID: 19670250

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.

Optical Imaging of the Peri-tumoral Inflammatory Response in Breast Cancer

Journal of Translational Medicine. 2009  |  Pubmed ID: 19906309

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.

An Optical Imaging Method to Monitor Stem Cell Migration in a Model of Immune-mediated Arthritis

Optics Express. Dec, 2009  |  Pubmed ID: 20052149

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.

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. 2010  |  Pubmed ID: 20370988

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.

Breast Cancers: MR Imaging of Folate-receptor Expression with the Folate-specific Nanoparticle P1133

Radiology. May, 2010  |  Pubmed ID: 20413763

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.

Indocyanine Green-enhanced Imaging of Antigen-induced Arthritis with an Integrated Optical Imaging/radiography System

Arthritis and Rheumatism. Aug, 2010  |  Pubmed ID: 20506388

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.

Monitoring of Natural Killer Cell Immunotherapy Using Noninvasive Imaging Modalities

Cancer Research. Aug, 2010  |  Pubmed ID: 20631071

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.

MR Signal Characteristics of Viable and Apoptotic Human Mesenchymal Stem Cells in Matrix-associated Stem Cell Implants for Treatment of Osteoarthritis

Investigative Radiology. Oct, 2010  |  Pubmed ID: 20808236

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.

A Phase I Study of Zoledronic Acid and Low-dose Cyclophosphamide in Recurrent/refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) Study

Pediatric Blood & Cancer. Nov, 2010  |  Pubmed ID: 21077182

BACKGROUND: Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. PROCEDURE: Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m(2)/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. RESULTS: Twenty-one patients, median age 7.5 (range 0.8-25.6) years were treated with 2 mg/m(2) (n = 4), 3 mg/m(2) (n = 3), or 4 mg/m(2) (n = 14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (grade 3 hypophosphatemia) occurred at 4 mg/m(2) zoledronic acid. Other grades 3-4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 1), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. CONCLUSIONS: Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m(2) every 28 days. Pediatr Blood Cancer. © 2010 Wiley-Liss, Inc.

Accelerated Stem Cell Labeling with Ferucarbotran and Protamine

European Radiology. Mar, 2010  |  Pubmed ID: 19756632

To develop and characterize a clinically applicable, fast and efficient method for stem cell labeling with ferucarbotran and protamine for depiction with clinical MRI.

A Phase I Study of Zoledronic Acid and Low-dose Cyclophosphamide in Recurrent/refractory Neuroblastoma: a New Approaches to Neuroblastoma Therapy (NANT) Study

Pediatric Blood & Cancer. Aug, 2011  |  Pubmed ID: 21671363

Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials.

MRI of Tumor-associated Macrophages with Clinically Applicable Iron Oxide Nanoparticles

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2011  |  Pubmed ID: 21791632

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.

Magnetic Resonance Imaging of Ferumoxide-Labeled Mesenchymal Stem Cells in Cartilage Defects: In Vitro and In Vivo Investigations

Molecular Imaging. Sep, 2011  |  Pubmed ID: 21955668

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 T(2) 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.

Labeling Human Mesenchymal Stem Cells with Fluorescent Contrast Agents: the Biological Impact

Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging. Feb, 2011  |  Pubmed ID: 20379785

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.

Engineering Stem Cells for Treatment of Osteochondral Defects

Skeletal Radiology. Jan, 2012  |  Pubmed ID: 22072236

Differentiation of Normal Thymus from Anterior Mediastinal Lymphoma and Lymphoma Recurrence at Pediatric PET/CT

Radiology. Feb, 2012  |  Pubmed ID: 22157202

Purpose: 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. Materials and Methods: 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 (SUV(t)), and bone marrow at the level of the fifth lumbar vertebra (SUV(b)) on PET images. Quantitative parameters were compared by using an analysis of variance test. Results: Mean prechemotherapy SUV(t) was 4.82 for group A, 8.45 for group B, 2.00 for group C, and 2.09 for group D. Mean postchemotherapy SUV(t) for group B was 4.74. Thymic rebound (mean SUV(t), 2.89) was seen in 44% of patients at a mean interval of 10 months from the end of chemotherapy. The differences between prechemotherapy SUV(t) of mediastinal lymphoma and normal thymus and postchemotherapy SUV(t) of lymphoma recurrence and thymic rebound were highly significant (P < .001). Conclusion: SUV(t) is a sensitive predictor for differentiation of normal thymus or thymic rebound from mediastinal lymphoma. SUV(t) of 3.4 or higher is a strong predictor of mediastinal lymphoma. © RSNA, 2011.