Otto C. Boerman

Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques.

Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin.Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin.

Spatial Resolution and Sensitivity of the Inveon Small-Animal PET Scanner

The Inveon small-animal PET scanner is characterized by a large, 127-mm axial length and a 161-mm crystal ring diameter. The associated high sensitivity is obtained by using all lines of response (LORs) up to the maximum ring difference (MRD) of 79, for which the most oblique LORs form acceptance angles of 38.3° with transaxial planes. The result is 2 phenomena that are normally not encountered in PET scanners: a parallax or depth-of-interaction effect in the axial direction and the breakdown of Fourier rebinning (FORE). Both effects cause a deterioration of axial spatial resolution. Limiting the MRD to smaller values reduces this axial blurring at the cost of sensitivity. Alternatively, 3-dimensional (3D) reconstruction techniques can be used in which the rebinning step is absent. The aim of this study was to experimentally determine the spatial resolution and sensitivity of the Inveon for its whole field of view (FOV). Methods: Spatial resolution and sensitivity were measured using filtered backprojection (FBP) with FORE, FBP with LOR angle-weighted adapted FORE (AFORE), and 3D ordered-subset expectation maximization followed by maximum a posteriori reconstruction (OSEM3D/MAP). Results: Tangential and radial full width at half maximum (FWHM) showed almost no dependence on the MRD using FORE and FBP. Tangential FWHMs were 1.5 mm in the center of the FOV (CFOV) and 1.8 mm at the edge of the FOV (EFOV). Radial FWHMs were 1.5 and 3.0 mm in the CFOV and EFOV, respectively. In contrast, axial FWHMs increased with the MRD and ranged between 1.1 and 2.0 mm in the CFOV and between 1.5 and 2.7 mm in the EFOV for a MRD between 1 and 79. AFORE improved the axial resolution for a large part of the FOV, but image noise increased. OSEM3D/MAP yielded uniform spatial resolution in all directions, with an average FWHM of 1.65 ± 0.06 mm. Sensitivity in the CFOV for the default energy and coincidence time window was 0.068; peak sensitivity was 0.111. Conclusion: The Inveon showed high spatial resolution and high sensitivity, both of which can be maintained using OSEM3D/MAP reconstruction instead of rebinning and 2D algorithms.

PET and SPECT in Osteomyelitis and Prosthetic Bone and Joint Infections: A Systematic Review

OBJECTIVE To review the literature on diagnostic accuracy and clinical value of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for imaging of bone and joint infections. METHODS The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on osteomyelitis and prosthetic bone and joint infections using specific guidelines with MeSH-terms, truncations, and completion using cross-references. RESULTS In 44 original articles (15 for SPECT and 29 for (18)F-fluorodeoxyglucose [FDG]-PET) on osteomyelitis and prosthetic bone and joint infection, 1634 patients were included (580 patients SPECT, 1054 patients FDG-PET). Level of evidence (Oxford criteria) was 2-3b. For SPECT, the highest diagnostic accuracy of 95% for diagnosis of bone and joint infections is achieved with combined (111)In-WBC and (99m)Tc-sulfur colloid. Acceptable diagnostic accuracy was also obtained with (99m)Tc-WBC or (111)In-WBC combined with (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). FDG-PET is useful for diagnosis of osteomyelitis with a sensitivity and specificity generally over 95%. In patients with orthopedic implant infections, sensitivity varies widely from 28% to 91% and specificity from 9% to 97%. This variation in FDG-PET performance in orthopedic implant infections depends largely on the (use of different) criteria to diagnose infection. Determination of the best criteria is still a matter of debate. CONCLUSIONS SPECT/computed tomography (CT) with (111)In-WBC combined with (99m)Tc-MDP or (99m)Tc-sulfur colloid seems to be the best imaging technique for diagnosis of bone and joint infections. FDG-PET is also useful for diagnosis of osteomyelitis with improved spatial resolution over SPECT imaging, allowing more accurate localization. Localization can be further improved by adding CT. Diagnosis of orthopedic implant infections with FDG-PET depends strongly on the localization of the implant and the criteria used to diagnose infection. Confirmation of well defined criteria to diagnose infection on FDG-PET in patients with metallic implants is thus of paramount importance for optimal diagnosis.

Carbonic Anhydrase IX in Renal Cell Carcinoma: Implications for Prognosis, Diagnosis, and Therapy

CONTEXT The clinical management of patients with renal cell carcinoma (RCC) remains difficult, and the development of new diagnostic, prognostic, and therapeutic tools is still required. OBJECTIVE To review the current knowledge on the RCC-associated antigen carbonic anhydrase IX (CAIX) and provide evidence for how this antigen may aid in the clinical management of RCC. EVIDENCE ACQUISITION Clinical papers describing diagnostic, prognostic, and/or therapeutic applications of CAIX in RCC were selected from the Pubmed database. The search was manually augmented by reviewing the reference lists of articles. EVIDENCE SYNTHESIS Expression of CAIX is regulated by the Von Hippel Lindau (VHL) protein (pVHL). Because of the invariable VHL mutational loss in clear-cell RCC (ccRCC) patients, CAIX expression is ubiquitous in ccRCC. Determination of CAIX expression in nephrectomy specimens of RCC patients improves prognostic accuracy; high CAIX expression appears to correlate with a favourable prognosis and a greater likelihood of response to systemic treatment for metastatic disease. Therefore, CAIX expression might be used to stratify metastatic ccRCC (mRCC) patients for systemic treatment. When incorporated into the RCC nomogram, CAIX expression seems to improve diagnostic accuracy for primary RCC as well as mRCC patients, but further evidence is required. Clinical studies with the CAIX-specific monoclonal antibody (mAb) cG250 have provided unequivocal evidence that ccRCC lesions can be imaged with radiolabeled cG250. Results are awaited of a large, randomised trial that aims to establish the value of cG250 imaging for primary RCC. The outcome of another large, placebo-controlled study is awaited to establish the usefulness of CAIX-targeted therapy in the adjuvant setting. Therapeutic trials with high-dose radiolabeled cG250 and CAIX-loaded dendritic cells in mRCC patients are still in phase 1 or 2. CONCLUSIONS CAIX improves diagnostic accuracy and is an attractive target for imaging of and therapy for ccRCC.

Long-lived positron emitters zirconium-89 and iodine-124 for scouting of therapeutic radioimmunoconjugates with PET

Antibody-PET imaging might be of value for the selection of radioimmunotherapy (RIT) candidates to confirm tumor targeting and to estimate radiation doses to tumor and normal tissues. One of the requirements to be set for such a scouting procedure is that the biodistributions of the diagnostic and therapeutic radioimmunoconjugates should be similar. In the present study we evaluated the potential of the positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I) for this approach, as these radionuclides have a relatively long half-life that matches with the kinetics of MAbs in vivo (t(1/2) 3.27 and 4.18 days, respectively). After radiolabeling of the head and neck squamous cell carcinoma (HNSCC)-selective chimeric antibody (cMAb) U36, the biodistribution of two diagnostic (cMAb U36-N-sucDf-(89)Zr and cMAb U36-(124)I) and three therapeutic radioimmunoconjugates (cMAb U36-p-SCN-Bz-DOTA-(88)Y-with (88)Y being substitute for (90)Y, cMAb U36-(131)I, and cMAb U36-MAG3-(186)Re) was assessed in mice with HNSCC-xenografts, at 24, 48, and 72 hours after injection. Two patterns of biodistribution were observed, one pattern matching for (89)Zr- and (88)Y-labeled cMAb U36 and one pattern matching for (124)I-, (131)I-, and (186)Re-cMAb U36. The most remarkable differences between both patterns were observed for uptake in tumor and liver. Tumor uptake levels were 23.2 +/- 0.5 and 24.1 +/- 0.7%ID/g for the (89)Zr- and (88)Y-cMAb U36 and 16.0 +/- 0.8, 15.7 +/- 0.79 and 17.1 +/- 1.6%ID/g for (124)I-, (131)I-, and (186)Re-cMAb U36-conjugates, respectively, at 72 hours after injection. For liver these values were 6.9 +/- 0.8 ((89)Zr), 6.2 +/- 0.8 ((88)Y), 1.7 +/- 0.1 ((124)I), 1.6 +/- 0.1 ((131)I), and 2.3 +/- 0.1 ((186)Re), respectively. These preliminary data justify the further development of antibody-PET with (89)Zr-labeled MAbs for scouting of therapeutic doses of (90)Y-labeled MAbs. In such approach (124)I-labeled MAbs are most suitable for scouting of (131)I- and (186)Re-labeled MAbs.

Comparison of micro- vs. nanostructured colloidal gelatin gels for sustained delivery of osteogenic proteins: Bone morphogenetic protein-2 and alkaline phosphatase

Colloidal gels have recently emerged as a promising new class of materials for regenerative medicine by employing micro- and nanospheres as building blocks to assemble into integral scaffolds. To this end, physically crosslinked particulate networks are formed that are injectable yet cohesive. By varying the physicochemical properties of different particle populations, the suitability of colloidal gels for programmed delivery of multiple therapeutic proteins is superior over conventional monolithic gels that lack this strong capacity for controlled drug release. Colloidal gels made of biodegradable polymer micro- or nanospheres have been widely investigated over the past few years, but a direct comparison between micro- vs. nanostructured colloidal gels has not been made yet. Therefore, the current study has compared the viscoelastic properties and capacity for drug release of colloidal gels made of oppositely charged gelatin microspheres vs. nanospheres. Viscoelastic properties of the colloidal gelatin gels were characterized by rheology and simple injectability tests, and in vitro release of two selected osteogenic proteins (i.e. bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP)) from the colloidal gelatin gels was evaluated using radiolabeled BMP-2 and ALP. Nanostructured colloidal gelatin gels displayed superior viscoelastic properties over microsphere-based gels in terms of elasticity, injectability, structural integrity, and self-healing behavior upon severe network destruction. In contrast, microstructured colloidal gelatin gels exhibited poor gel strength and integrity, unfavorable injectability, and did not recover after shearing, resulting from the poor gel cohesion due to insufficiently strong interparticle forces. Regarding the capacity for drug delivery, sustained growth factor (BMP-2) release was obtained for both micro- and nanosphere-based gels, the kinetics of which were mainly depending on the particle size of gelatin spheres with the same crosslinking density. Therefore, the optimal gelatin carrier for drug delivery in terms of particle size and crosslinking density still needs to be established for specific clinical indications that require either short-term or long-term release. It can be concluded that nanostructured colloidal gelatin gels show great potential for sustained delivery of therapeutic proteins, whereas microstructured colloidal gelatin gels are not sufficiently cohesive as injectables for biomedical applications.

Correlation of [18F]FMISO autoradiography and pimonodazole immunohistochemistry in human head and neck carcinoma xenografts.

PurposeTumour cell hypoxia is a common feature in solid tumours adversely affecting radiosensitivity and chemosensitivity in head and neck squamous cell carcinomas. Positron emission tomography (PET) using the tracer [18F]fluoromisonidazole ([18F]FMISO) is most frequently used for non-invasive evaluation of hypoxia in human tumours. A series of ten human head and neck xenograft tumour lines was used to validate [18F]FMISO as hypoxia marker at the microregional level.MethodsAutoradiography after injection of [18F]FMISO was compared with immunohistochemical staining for the hypoxic cell marker pimonidazole in the same tumour sections of ten different human head and neck xenograft tumour lines. The methods were compared: first, qualitatively considering the microarchitecture; second, by obtaining a pixel-by-pixel correlation of both markers at the microregional level; third, by measuring the signal intensity of both images; and fourth, by calculating the hypoxic fractions by pimonidazole labelling.ResultsThe pattern of [18F]FMISO signal was dependent on the distribution of hypoxia at the microregional level. The comparison of [18F]FMISO autoradiography and pimonidazole immunohistochemistry by pixel-by-pixel analysis revealed moderate correlations. In five tumour lines, a significant correlation between the mean [18F]FMISO and pimonidazole signal intensity was found (range, r2 = 0.91 to r2 = 0.99). Comparison of the tumour lines with respect to the microregional distribution pattern of hypoxia revealed that the correlation between the mean signal intensities strongly depended on the microarchitecture. Overall, a weak but significant correlation between hypoxic fractions based on pimonidazole labeling and the mean [18F]FMISO signal intensity was observed (r2 = 0.18, p = 0.02). For the three tumour models with a ribbon-like microregional distribution pattern of hypoxia, the correlation between the hypoxic fraction and the mean [18F]FMISO signal intensity was much stronger and more significant (r2 = 0.73, p < 0.001) than for the tumours with a more homogenous, patchy, microregional distribution pattern of hypoxia.ConclusionDifferent patterns of [18F]FMISO accumulation dependent on the underlying microregional distribution of hypoxia were found in ten head and neck xenograft tumours. A weak albeit significant correlation was found between the mean [18F]FMISO signal intensity and the hypoxic fraction of the tumours. In larger clinical tumours, [18F]FMISO–PET provides information on the tumour oxygenation status on a global level, facilitating dose painting in radiation treatment planning. However, caution must be taken when studying small tumour subvolumes as accumulation of the tracer depends on the presence of hypoxia and on the tumour microarchitecture.

Application of Metal‐Free Triazole Formation in the Synthesis of Cyclic RGD–DTPA Conjugates

The tandem 1,3‐dipolar cycloaddition‐retro‐Diels–Alder (tandem crDA) reaction is presented as a versatile method for metal‐free chemoselective conjugation of a DTPA radiolabel to N‐δ‐azido‐cyclo(‐Arg‐Gly‐Asp‐d‐Phe‐Orn‐) via oxanorbornadiene derivatives. To this end, the behavior of several trifluoromethyl‐substituted oxanorbornadiene derivatives in the 1,3‐dipolar cycloaddition was studied and optimized to give a clean and efficient method for bio‐orthogonal ligation in an aqueous environment. After radioisotope treatment, the resulting 111In‐labeled c(RGD)‐CF3‐triazole‐DTPA conjugate was subjected to preliminary biological evaluation and showed high affinity for αvβ3 (IC50=192 nM) and favorable pharmacokinetics.

Reducing renal uptake of radiolabeled peptides using albumin fragments.

In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of 111In-diethylenetriaminepentaacetic acid (DTPA)-d-Phe1-octreotide (111In-octreotide), [Lys40(aminohexoic acid-DTPA-111In)NH2]-exendin-4 (111In-exendin), and 111In-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA)-Glu1-minigastrin (111In-minigastrin). Methods: The effects of albumin and FRALB on megalin-associated binding of 111In-octreotide, 111In-exendin, and 111In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of 111In-albumin and 111In-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of 111In-octreotide, 111In-exendin, and 111In-minigastrin. Results: FRALB significantly reduced binding and uptake of 111In-octreotide, 111In-exendin, and 111In-minigastrin by BN16 cells. In rats, renal uptake of 111In-labeled FRALB was significantly higher than that of 111In-labeled intact albumin (P < 0.001). FRALB administration effectively reduced renal uptake of 111In-octreotide, 111In-exendin, and 111In-minigastrin. Administration of 1–2 mg of FRALB reduced renal uptake of 111In-octreotide as efficiently as 80 mg of lysine. Conclusion: Renal uptake of 111In-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted.

Radiolabelled peptides for oncological diagnosis

Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The 111In-labelled somatostatin analogue octreotide (OctreoScan™) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours.