Heike E. Daldrup-Link

FDG-PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy

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 Ewings 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 Ewings 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 Ewings 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 Ewings 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.

FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: Comparison with spiral CT

BACKGROUND 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. PATIENTS AND METHODS In 71 patients with histologically confirmed malignant primary bone tumors (32 osteosarcomas, 39 Ewings 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. RESULTS 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. CONCLUSIONS 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.

T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical MR scanning.

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 (2.5×107-0.3×107 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 2.5×107 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.

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

Purpose: 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. Experimental Design: 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. Results: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. Conclusion: 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. Clin Cancer Res; 17(17); 5695–704. ©2011 AACR.

CT of metal implants : Reduction of artifacts using an extended CT scale technique

PURPOSE 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. METHOD 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. RESULTS 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). CONCLUSION 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.

Ultrasmall supraparamagnetic iron oxide-enhanced magnetic resonance imaging of antigen-induced arthritis: a comparative study between SHU 555 C, ferumoxtran-10, and ferumoxytol.

Objectives:We sought to compare the ability of 3 ultrasmall superparamagnetic iron oxides (USPIOs) to detect and characterize antigen-induced arthritis with MR imaging. Materials and Methods: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 μmol 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. Results:Quantitative signal to noise ratio and ΔSI 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 ΔSI 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. Conclusions: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.

Breast cancers: MR imaging of folate-receptor expression with the folate-specific nanoparticle P1133.

PURPOSE 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

MR imaging of therapy-induced changes of bone marrow

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.

Macromolecular contrast agents for MR mammography: current status.

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.

Ionising radiation-free whole-body MRI versus 18F-fluorodeoxyglucose PET/CT scans for children and young adults with cancer: A prospective, non-randomised, single-centre study

BACKGROUND 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. METHODS 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 Cohens 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. FINDINGS 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. INTERPRETATION 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. FUNDING Thrasher Research Fund and Clinical Health Research Institute at Stanford University.