Utility of fluorodeoxyglucose-PET in patients with differentiated thyroid carcinoma.

AIM: In differentiated thyroid carcinoma, persistent plasma thyroglobulin (Tg) is a specific marker for persistent or recurrent disease after thyroidectomy and radioiodine ablation. When Tg remains elevated and no substrate can be found on whole-body radioiodine imaging (131I-WBS), or even when recurrent disease is suspected with normal Tg, conventional imaging (CI) is often insufficient. As fluorodeoxyglucose (FDG)-PET has proven to be an effective modality for detecting various types of cancer, the utility of FDG-PET was analysed and compared with CI in this retrospective study in patients with differentiated thyroid cancer. PATIENTS AND METHODS: After total thyroidectomy and radioiodine ablation, 68 FDG-PET scans were performed in 39 patients with elevated Tg levels or clinical suspicion of recurrent disease. At the time of FDG-PET, 54 131I-WBS (in 30 patients) were negative, 14 (in 11 patients) were equivocal. Tg was normal at the time of 14 scans (10 patients) and elevated in 54 (in 33 patients). FDG-PET results were compared with histology, 131I-WBS and CI and clinical follow-up. Sensitivity and specificity were evaluated in various subgroups. RESULTS: Overall, there were 35 true-positive, two false-positive, 20 true-negative and three false-negative FDG-PET scans. In six of these cases (one true positive, five true negative) FDG-PET was repeated without intervention and in an additional eight FDG-PET scans no definite conformation of abnormal FDG-PET could be obtained, so these results were not used for statistical analysis. Sensitivity, specificity, PPV and NPV for the whole group were 92, 88, 94 and 83%, respectively. In 38 scans performed on 31 patients with elevated Tg levels, who were not known with recurrence, this was 84, 100, 100 and 75%, respectively. In 16 scans in 10 patients with known recurrence (all with elevated Tg), sensitivity and PPV were 100% without false-positive or false-negative results. When Tg was not detectable (14 scans in 10 patients), sensitivity, specificity, PPV and NPV were 100, 75, 60 and 100%, respectively. After 35 FDG-PET scans (51%), there was a change in patient management by avoiding ineffective 131I treatment, by guiding surgical reintervention, or avoiding futile surgery. One FP FDG-PET resulted in an unnecessary surgical procedure. In 33 cases, FDG-PET did not lead to a change in treatment policy, which retrospectively would have been beneficial in six cases. CONCLUSION: FDG-PET affected patient management in patients with differentiated thyroid cancer and negative 131I-WBS, not only when Tg is elevated, but also when Tg is not detectable and therefore the use of FDG-PET as a diagnostic tool is justified in these patients.

Comparison of tumor volumes derived from glucose metabolic rate maps and SUV maps in dynamic 18F-FDG PET.

UNLABELLED: Tumor delineation using noninvasive medical imaging modalities is important to determine the target volume in radiation treatment planning and to evaluate treatment response. It is expected that combined use of CT and functional information from 18F-FDG PET will improve tumor delineation. However, until now, tumor delineation using PET has been based on static images of 18F-FDG standardized uptake values (SUVs). 18F-FDG uptake depends not only on tumor physiology but also on blood supply, distribution volume, and competitive uptake processes in other tissues. Moreover, 18F-FDG uptake in tumor tissue and in surrounding healthy tissue depends on the time after injection. Therefore, it is expected that the glucose metabolic rate (MRglu) derived from dynamic PET scans gives a better representation of the tumor activity than does SUV. The aim of this study was to determine tumor volumes in MRglu maps and to compare them with the values from SUV maps. METHODS: Twenty-nine lesions in 16 dynamic 18F-FDG PET scans in 13 patients with non-small cell lung carcinoma were analyzed. MRglu values were calculated on a voxel-by-voxel basis using the standard 2-compartment 18F-FDG model with trapping in the linear approximation (Patlak analysis). The blood input function was obtained by arterial sampling. Tumor volumes were determined in SUV maps of the last time frame and in MRglu maps using 3-dimensional isocontours at 50% of the maximum SUV and the maximum MRglu, respectively. RESULTS: Tumor volumes based on SUV contouring ranged from 1.31 to 52.16 cm3, with a median of 8.57 cm3. Volumes based on MRglu ranged from 0.95 to 37.29 cm3, with a median of 3.14 cm3. For all lesions, the MRglu volumes were significantly smaller than the SUV volumes. The percentage differences (defined as 100% x (V MRglu - V SUV)/V SUV, where V is volume) ranged from -12.8% to -84.8%, with a median of -32.8%. CONCLUSION: Tumor volumes from MRglu maps were significantly smaller than SUV-based volumes. These findings can be of importance for PET-based radiotherapy planning and therapy response monitoring.

Chemotherapy response evaluation with 18F-FDG PET in patients with non-small cell lung cancer.

UNLABELLED: The aim of this prospective study was to evaluate the value of (18)F-FDG PET for the assessment of chemotherapy response in patients with non-small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. METHODS: In 51 patients, dynamic (18)F-FDG PET was performed before and at 5-8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MR(Glu)]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MR(Glu) and SUV were calculated using Kaplan-Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. RESULTS: When stratifying at the median value of DeltaMR(Glu) and DeltaSUV, the difference in overall survival (P = 0.017 for DeltaMR(Glu), P = 0.018 for DeltaSUV) and progression-free survival (P = 0.002 for DeltaMR(Glu), P = 0.0009 for DeltaSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for DeltaSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). CONCLUSION: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by (18)F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of (18)F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MR(Glu)) in this patient population.

Predictive and prognostic value of FDG-PET in nonsmall-cell lung cancer: a systematic review.

For several years, molecular imaging with (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) has become part of the standard of care in presurgical staging of patients with nonsmall-cell lung cancer (NSCLC), focusing on the detection of malignant lesions at early stages, early detection of recurrence, and metastatic spread. Currently, there is an increasing interest in the role of FDG-PET beyond staging, such as the evaluation of biological characteristics of the tumor and prediction of prognosis in the context of treatment stratification and the early assessment of tumor response to therapy. In this systematic review, the literature on the value of the evolving applications of FDG-PET as a marker for prediction (ie, therapy response monitoring) and prognosis in NSCLC is addressed, divided in sections on the predictive value of FDG-PET in locally advanced and advanced disease, the prognostic value of FDG-PET at diagnosis, after induction treatment, and in recurrent disease. Furthermore, the background and recommendations for the application of FDG-PET for these indications will be discussed.

Development and application of peptide-based radiopharmaceuticals.

During the past decade, radiolabeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for tumor diagnosis and therapy. The specific receptor binding property of the ligand can be exploited by labeling the ligand with a radionuclide and using the radiolabeled ligand as a vehicle to guide the radioactivity to the tissues expressing a particular receptor. The concept of using radiolabeled receptor binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. Receptor binding peptides labeled with gamma emitters ((123)I, (111)In, (99m)Tc) can visualize receptor-expressing tissues, a technique referred to as peptide-receptor radionuclide imaging (PRRI). In addition, labeled with beta emitters ((131)I, (90)Y, (188)Re, (177)Lu) these peptides have the potential to irradiate receptor-expressing tissues, an approach referred to as peptide-receptor radionuclide therapy (PRRT). The first and most successful imaging agent to date is the somatostatin analog octreotide. It is used for somatostatin receptor scintigraphy and PRRT of neuroendocrine tumors. Other peptides such as Minigastrin, GLP-1, CCK, bombesin, substance P, neurotensin, and RGD peptides are currently under development or undergoing clinical trials. In this review, an overview of the criteria of peptide ligand development, the selection of radioisotopes, labeling methods, and chemical aspects of radiopeptide synthesis is given. In addition, the current state of clinical use of radiopeptides for diagnosis and therapy of tumors is discussed.

PET imaging of infection with a HYNIC-conjugated LTB4 antagonist labeled with F-18 via hydrazone formation.

UNLABELLED: It was previously shown that the (99m)Tc-labeled hydrazinonicotinamide (HYNIC)-conjugated LTB4 antagonist MB81 visualized infectious foci in rabbits adequately and within a few hours after injection. Here, the bivalent HYNIC-conjugated LTB4 antagonist MB67 (analog of MB81) was fluorinated with (18)F via hydrazone formation and tested in vivo. METHODS: MB67 was [(18)F]-fluorinated via reaction of the [(18)F]-fluorinated intermediate p-[(18)F]-fluorobenzaldehyde ([(18)F]FB) and the HYNIC moiety of MB67 via hydrazone formation. For comparison, MB67 was also labeled with (99m)Tc. The biodistribution of (18)F- and (99m)Tc-labeled MB67 was investigated in rabbits with intramuscular infection. RESULTS: [(18)F]-MB67 was obtained at a maximum specific activity of 1200 GBq/mmol and proved to be stable in phosphate buffered saline (PBS) at 37 degrees C for at least 4 h. PET images obtained with [(18)F]-MB67 clearly delineated the abscess at 2 and 4 h pi. Counting of dissected tissues at 4 h pi revealed an abscess uptake of 0.073+/-0.005 %ID/g, as compared to 0.160+/-0.010 %ID/g for the (99m)Tc-labeled analog. Abscess-to-muscle ratios were 23+/-4 for [(18)F]-MB67 and 35+/-9 for [(99m)Tc]-MB67. CONCLUSION: The present study showed the feasibility of a new [(18)F]-labeling methodology and its application in the production of a new PET tracer for imaging of infection, [(18)F]-MB67.

Evaluation of image registration in PET/CT of the liver and recommendations for optimized imaging.

UNLABELLED: Multimodality PET/CT of the liver can be performed with an integrated (hybrid) PET/CT scanner or with software fusion of dedicated PET and CT. Accurate anatomic correlation and good image quality of both modalities are important prerequisites, regardless of the applied method. Registration accuracy is influenced by breathing motion differences on PET and CT, which may also have impact on (attenuation correction-related) artifacts, especially in the upper abdomen. The impact of these issues was evaluated for both hybrid PET/CT and software fusion, focused on imaging of the liver. METHODS: Thirty patients underwent hybrid PET/CT, 20 with CT during expiration breath-hold (EB) and 10 with CT during free breathing (FB). Ten additional patients underwent software fusion of dedicated PET and dedicated expiration breath-hold CT (SF). The image registration accuracy was evaluated at the location of liver borders on CT and uncorrected PET images and at the location of liver lesions. Attenuation-correction artifacts were evaluated by comparison of liver borders on uncorrected and attenuation-corrected PET images. CT images were evaluated for the presence of breathing artifacts. RESULTS: In EB, 40% of patients had an absolute registration error of the diaphragm in the craniocaudal direction of >1 cm (range, -16 to 44 mm), and 45% of lesions were mispositioned >1 cm. In 50% of cases, attenuation-correction artifacts caused a deformation of the liver dome on PET of >1 cm. Poor compliance to breath-hold instructions caused CT artifacts in 55% of cases. In FB, 30% had registration errors of >1 cm (range, -4 to 16 mm) and PET artifacts were less extensive, but all CT images had breathing artifacts. As SF allows independent alignment of PET and CT, no registration errors or artifacts of >1 cm of the diaphragm occurred. CONCLUSION: Hybrid PET/CT of the liver may have significant registration errors and artifacts related to breathing motion. The extent of these issues depends on the selected breathing protocol and the speed of the CT scanner. No protocol or scanner can guarantee perfect image fusion. On the basis of these findings, recommendations were formulated with regard to scanner requirements, breathing protocols, and reporting.

Multi-modality nuclear medicine imaging: artefacts, pitfalls and recommendations.

Multi-modality imaging is rapidly becoming an essential tool in oncology. Clinically, the best example of multimodality imaging is seen in the rapid evolution of hybrid positron emission tomography (PET)/computed tomography (CT) and single positron emission computed tomography (SPECT)/CT scanners. However, use of multi-modality imaging is prone to artefacts and pitfalls. Important artefacts that may lead to clinical misinterpretation result from the use of CT data to correct for attenuation and the existence of mismatches between the fused images, for example due to respiratory movement. Furthermore, for institutions who proceed from a standalone PET to a hybrid PET-CT, there is an issue of interchangeability between these systems, especially for quantitative studies. Another issue is visualisation: hospital PACS is not sufficiently capable of adequately viewing integrated images. This article reviews and illustrates the most common artefacts and pitfalls that can be encountered in multi-modality nuclear medicine imaging. For correct management of oncological patients it is essential to be able to detect and correctly interpret these artefacts and pitfalls. Therefore, solutions and recommendations to these problems are provided.

Impact of Ge-68/Ga-68-based versus CT-based attenuation correction on PET.

Transmission (Tx) scans are used in PET for attenuation correction (AC). For standalone PET this is typically done using Ge-68/Ga-68 sources, for PET-CT using CT. Therefore, standalone PET suffers from emission contamination during Tx scans, PET-CT does not. Here, we studied the effects of AC across the two systems. With a cylindrical phantom (Jaszczak Phantom, Data Spectrum Corp.) with hollow spheres (diameter 10-60 mm) two studies were performed. In the first study the hollow spheres were filled with 150 kBq/ml FDG and the background with 15 kBq/ml. In the second study we used 120 kBq/ml in the spheres and 50 kBq/ml in the background. Both a low and a high object-to-background ratio are studied this way. Multiple scans were acquired on a standalone PET and a PET-CT until 1% of the initial concentration remained. Activity concentration in the spheres and background was measured from the reconstructed images and compared to the actual concentration. For standalone PET, emission scans were reconstructed using hot Tx (emission contaminated) and cold Tx (not contaminated). Uniformity within the spheres was investigated by profile analysis. For PET-CT, the concentration in the big spheres (> 16 mm) was recovered. For the smaller spheres, recovery was insufficient due to partial volume effects. For standalone PET the recoveries of the spheres (> 16 mm) were 20% (first study) and 13% (second study) lower than the actual concentration. Using hot Tx, underestimation of activity concentration was up to > 50%. Nonuniformities within the biggest spheres were up to 35%, 12%, and 5% (first study), using standalone PET with hot Tx, cold Tx, and using PET-CT, respectively. Due to contamination of AC by emission photons, standalone PET results in a bias in the activity concentration and uniformity. Especially when patients get follow-up PET scans on both standalone PET and PET-CT, this may lead to misinterpretation.

99mTc-labeled interleukin 8 for the scintigraphic detection of infection and inflammation: first clinical evaluation.

UNLABELLED: Interleukin 8 (IL-8) is a chemotactic cytokine that binds with a high affinity to receptors expressed on neutrophils. Previous studies with various animal models showed that (99m)Tc-labeled IL-8 accumulates specifically and rapidly in infectious and inflammatory foci. The aims of the present study were to evaluate the safety of IL-8 in humans and to assess the value of (99m)Tc-IL-8 scintigraphy in patients with suspected localized infections. METHODS: (99m)Tc-IL-8 was intravenously injected at 400 MBq into 20 patients with various suspected localized infections. Patients were monitored for IL-8-related side effects for 4 h. Whole-body imaging was performed directly after injection and at 4 h after injection. Imaging after 24 h was performed for the first 7 patients and for subsequent patients when the results of (99m)Tc-IL-8 scintigraphy at 4 h after injection were normal or equivocal. Blood was drawn at several time points to determine the total number of leukocytes and leukocyte differentiation (all patients) and to determine pharmacokinetics (6 patients). RESULTS: (99m)Tc-IL-8 scintigraphy was performed for 20 patients (13 men and 7 women) with a mean age of 60 y (range, 21-76 y). No significant side effects were noted. Patients had suspected joint prosthesis infections (n = 9), osteomyelitis (n = 8), liver abscess (n = 1), and soft-tissue infections (n = 2). (99m)Tc-IL-8 was rapidly cleared from the blood and most other organs. In 10 of 12 patients with infections, (99m)Tc-IL-8 localized the infection at 4 h after injection. In 1 patient with vertebral osteomyelitis and in 1 patient with an infected knee prosthesis, (99m)Tc-IL-8 scintigraphy results were false-negative. In 8 patients with noninfectious disorders, no focal accumulation of (99m)Tc-IL-8 was found. CONCLUSION: Injection of (99m)Tc-IL-8 is well tolerated. (99m)Tc-IL-8 scintigraphy is a promising new tool for the detection of infections in patients as early as 4 h after injection.

Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: implications for tumor targeting and tumor imaging purposes.

This report describes the design and synthesis of a series of alpha(V)beta(3) integrin-directed monomeric, dimeric and tetrameric cyclo[Arg-Gly-Asp-d-Phe-Lys] dendrimers using "click chemistry". It was found that the unprotected N-epsilon-azido derivative of cyclo[Arg-Gly-Asp-d-Phe-Lys] underwent a highly chemoselective conjugation to amino acid-based dendrimers bearing terminal alkynes using a microwave-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition. The alpha(V)beta(3) binding characteristics of the dendrimers were determined in vitro and their in vivoalpha(V)beta(3) targeting properties were assessed in nude mice with subcutaneously growing human SK-RC-52 tumors. The multivalent RGD-dendrimers were found to have enhanced affinity toward the alpha(V)beta(3) integrin receptor as compared to the monomeric derivative as determined in an in vitro binding assay. In case of the DOTA-conjugated (111)In-labeled RGD-dendrimers, it was found that the radiolabeled multimeric dendrimers showed specifically enhanced uptake in alpha(V)beta(3) integrin expressing tumors in vivo. These studies showed that the tetrameric RGD-dendrimer had better tumor targeting properties than its dimeric and monomeric congeners.

Effects of linker variation on the in vitro and in vivo characteristics of an 111In-labeled RGD peptide.

INTRODUCTION: Due to the selective expression of the alpha(v)beta3 integrin in tumors, radiolabeled arginine-glycine-aspartic acid (RGD) peptides are attractive candidates for tumor targeting. Minor modifications of these peptides could have a major impact on in vivo characteristics. In this study, we systematically investigated the effects of linker modification between two cyclic RGD sequences and DOTA (1,4,7,10-tetraazadodecane-N,N',N",N'''-tetraacetic acid) on the in vitro and in vivo characteristics of the tracer. METHODS: A dimeric RGD peptide was synthesized and conjugated either directly with DOTA or via different linkers: PEG4 (polyethylene glycol), glutamic acid or lysine. The RGD peptides were radiolabeled with 111In, and their in vitro and in vivo alpha(v)beta3-binding characteristics were determined. RESULTS: LogP values varied between -2.82+/-0.06 and -3.95+/-0.33. The IC50 values for DOTA-E-[c(RGDfK)]2, DOTA-PEG4-E-[c(RGDfK)]2, DOTA-E-E-[c(RGDfK)]2 and DOTA-K-E-[c(RGDfK)]2 were comparable. Two hours after injection, the tumor uptakes of the 111In-labeled compounds were not significantly different. The kidney accumulation of [111In]-DOTA-K-E-[c(RGDfK)]2 [4.05+/-0.20% of the injected dose per gram (ID/g)] was significantly higher as compared with that of [111In]-DOTA-E-[c(RGDfK)]2 (2.63+/-0.19% ID/g; P<.05) as well as that of [111In]-DOTA-E-E-[c(RGDfK)]2 (2.16+/-0.21% ID/g; P<.01). The liver uptake of [111In]-DOTA-E-E-[c(RGDfK)]2 (2.12+/-0.09% ID/g) was significantly higher as compared with that of [111In]-DOTA-E-[c(RGDfK)]2 (1.64+/-0.1% ID/g; P<.05) as well as that of [111In]-DOTA-K-E-[c(RGDfK)]2 (1.52+/-0.04% ID/g; P<.01). CONCLUSIONS: Linker variation did not affect affinity for alpha(v)beta3 and tumor uptake. Insertion of lysine caused enhanced kidney retention; that of glutamic acid also resulted in enhanced retention in the kidneys. PEG4 appeared to be the most suitable linker as compared with glutamic acid and lysine because it has the highest tumor-to-blood ratio and the lowest uptake in the kidney and liver.

Alpha v beta 3 integrin-targeting of intraperitoneally growing tumors with a radiolabeled RGD peptide.

Ovarian cancer is the fourth most common cause of cancer deaths among females in the western world after cancer of the breast, colon and lung. The inability to control the disease within the peritoneal cavity is the major cause of treatment failure in patients with ovarian cancer. The majority of ovarian carcinomas express the alpha(v)beta(3) integrin. Here we studied the tumor targeting potential of an (111)In-labeled cyclic RGD peptide in athymic BALB/c mice with intraperitoneally (i.p.) growing NIH:OVCAR-3 human ovarian carcinoma tumors. The cyclic RGD peptide, c(RGDfK)E, was synthesized, conjugated with DOTA and radiolabeled with (111)In. The targeting potential of (111)In-DOTA-E-c(RGDfK) was studied in athymic mice with i.p. growing NIH:OVCAR-3 xenografts and the optimal dose of this compound was determined (0.01 microg up to 10 microg). The biodistribution at optimal peptide dose was determined at various time points (0.5 up to 72 hr). Furthermore, the therapeutic potential of (177)Lu-DOTA-E-c(RGDfK) was studied in this model. Two hours after i.p. administration, (111)In-DOTA-E-c(RGDfK) showed high and specific uptake in the i.p. growing tumors. Optimal uptake in the i.p. growing tumors was observed at a 0.03-0.1 microg dose range. Tumor uptake of (111)In-DOTA-E-c(RGDfK) peaked 4 hr p.i. [(38.8 +/- 2.7)% ID/g], gradually decreasing at later time points [(24.0 +/- 4.1)% ID/g at 48 hr p.i.]. Intraperitoneal growth of OVCAR-3 could be significantly delayed by injecting 37 MBq (177)Lu-labeled peptide i.p. Radiolabeled DOTA-E-c(RGDfK) is suitable for targeting of i.p. growing tumors and potentially can be used for peptide receptor radionuclide therapy of these tumors.

Improved targeting of the alpha(v)beta (3) integrin by multimerisation of RGD peptides.

PURPOSE: The integrin alpha(v)beta(3) is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of alpha(v)beta(3) in tumours, alpha(v)beta(3) is considered a suitable receptor for tumour targeting. In this study the alpha(v)beta(3) binding characteristics of an (111)In-labelled monomeric, dimeric and tetrameric RGD analogue were compared. METHODS: A monomeric (E-c(RGDfK)), dimeric (E-[c(RGDfK)](2)), and tetrameric (E{E[c(RGDfK)](2)}(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (111)In. In vitro alpha(v)beta(3) binding characteristics were determined in a competitive binding assay. In vivo alpha(v)beta(3) targeting characteristics of the compounds were assessed in mice with SK-RC-52 xenografts. RESULTS: The IC(50) values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2), and DOTA-E{E[c(RGDfK)](2)}(2)were 120 nM, 69.9 nM and 19.6 nM, respectively. At all time points, the tumour uptake of the dimer was significantly higher as compared to that of the monomer. At 8 h p.i., tumour uptake of the tetramer (7.40+/-1.12%ID/g) was significantly higher than that of the monomer (2.30+/-0.34%ID/g), p<0.001, and the dimer (5.17+/-1.22%ID/g), p<0.05. At 24 h p.i., the tumour uptake was significantly higher for the tetramer (6.82+/-1.41%ID/g) than for the dimer (4.22+/-0.96%ID/g), p<0.01, and the monomer (1.90+/-0.29%ID/g), p<0.001. CONCLUSION: Multimerisation of c(RGDfK) resulted in enhanced affinity for alpha(v)beta(3) as determined in vitro. Tumour uptake of a tetrameric RGD peptide was significantly higher than that of the monomeric and dimeric analogues, presumably owing to the enhanced statistical likelihood for rebinding to alpha(v)beta(3).

A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin.

PURPOSE: Since (18)F-fluorodeoxyglucose (FDG) accumulates in neoplastic cells and in activated inflammatory cells, positron emission tomography (PET) with FDG could be valuable in diagnosing patients with fever of unknown origin (FUO). The aim of this study was to validate the use of FDG-PET as part of a structured diagnostic protocol in the general patient population with FUO. METHODS: From December 2003 to July 2005, 70 patients with FUO were recruited from one university hospital (n=38) and five community hospitals (n=32). A structured diagnostic protocol including FDG-PET was used. A dedicated, full-ring PET scanner was used for data acquisition. FDG-PET scans were interpreted by two staff members of the department of nuclear medicine without further clinical information. The final clinical diagnosis was used for comparison with the FDG-PET results. RESULTS: Of all scans, 33% were clinically helpful. The contribution of FDG-PET to the final diagnosis did not differ significantly between patients diagnosed in the university hospital and patients diagnosed in the community hospitals. FDG-PET contributed significantly more often to the final diagnosis in patients with continuous fever than in patients with periodic fever. FDG-PET was not helpful in any of the patients with normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). CONCLUSION: FDG-PET is a valuable imaging technique as part of a diagnostic protocol in the general patient population with FUO and a raised ESR or CRP.

FDG-PET in colorectal cancer.

[18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a useful imaging tool in the evolving management of patients with colorectal carcinoma. This technique is able to measure and visualize metabolic changes in cancer cells. This feature results in the ability to distinguish viable tumor from scar tissue, in the detection of tumor foci at an earlier stage than possible by conventional anatomic imaging and in the measurement of alterations in tumor metabolism, indicative of tumor response to therapy. Nowadays, FDG-PET plays a pivotal role in staging patients before surgical resection of recurrence and metastases, in the localization of recurrence in patients with an unexplained rise in serum carcinoembryonic antigen and in assessment of residual masses after treatment. In the presurgical evaluation, FDG-PET may be best used in conjunction with anatomic imaging in order to combine the benefits of both anatomical (CT) and functional (PET) information, which leads to significant improvements in preoperative liver staging and preoperative judgment on the feasibility of resection. Integration of FDG-PET into the management algorithm of these categories of patients alters and improves therapeutic management, reduces morbidity due to futile surgery, leads to substantial cost savings and probably also to a better patient outcome. FDG-PET also appears to have great potential in monitoring the success of local ablative therapies soon after intervention and in the prediction and evaluation of response to radiotherapy, systemic therapy, and combinations thereof. This review aims to outline the current and future role of FDG-PET in the field of colorectal cancer.

Synthesis and biological evaluation of potent alphavbeta3-integrin receptor antagonists.

INTRODUCTION: alpha(v)beta(3) Integrin is expressed in sprouting endothelial cells in growing tumors, whereas it is absent in quiescent blood vessels. In addition, various tumor cell types express alpha(v)beta(3) integrin. alpha(v)beta(3) Integrin, a transmembrane heterodimeric protein, binds to the arginine-glycine-aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin and plays a pivotal role in invasion, proliferation and metastasis. Due to the selective expression of alpha(v)beta(3) integrin in tumors, radiolabeled RGD peptides and peptidomimetics are attractive candidates for tumor targeting. METHODS: A cyclic RGD peptide, a peptoid-peptide hybrid, an all-peptoid and a peptidomimetic compound were synthesized, conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and radiolabeled with (111)In. Their in vitro and in vivo alpha(v)beta(3)-binding characteristics were determined. RESULTS: IC(50) values were 236 nM for DOTA-E-c(RGDfK), 219 nM for DOTA-peptidomimetic, >10 mM for DOTA-all-peptoid and 9.25 mM for the peptoid-peptide hybrid DOTA-E-c(nRGDfK). (111)In-labeled compounds, except for [(111)In]DOTA-all-peptoid, showed specific uptake in human alpha(v)beta(3)-expressing tumors xenografted in athymic mice. Tumor uptake for [(111)In]DOTA-E-c(RGDfK) was 1.73+/-0.4% ID/g (2 h postinjection) and that of [(111)In]DOTA-peptidomimetic was 2.04+/-0.3% ID/g. Tumor uptake for the peptoid-peptide hybrid [(111)In]DOTA-E-c(nRGDfK) was markedly lower (0.45+/-0.07% ID/g). The all-peptoid [(111)In]DOTA-E-c(nRGnDnFnK) did not show specific uptake in tumors (0.11+/-0.04% ID/g). CONCLUSIONS: The peptidomimetic compound and the cyclic RGD peptide have a high affinity for alpha(v)beta(3) integrin, and these compounds have better tumor-targeting characteristics than the peptoid-peptide hybrid and the all-peptoid.

Targeting of biliary cancer with radiolabeled chimeric monoclonal antibody CG250.

OBJECTIVE: Carbonic anhydrase 9 recognized by chimeric monoclonal antibody cG250 is overexpressed on biliary cancers. The aim of this study was to determine the targeting of radiolabeled cG250 in patients with biliary cancer to explore a potential role of radioimmunotherapy. METHODS: Three (3) patients received a diagnostic dose 111In-cG250, and images were acquired 2 hours and 5 days after injection. Immediately after the last imaging session, 131I-cG250 was administered and images were acquired after 2 hours and 5 days. Visual and quantitative analyses was performed and tumor- to-background, tumor-to-normal liver-uptake ratios, and tumor uptake were calculated. RESULTS: Administration of 111In-cG250 in patients with biliary cancer did not reveal enhanced uptake in the cancer lesions on whole-body scans. The scans obtained after the 131I-cG250 administration showed slightly enhanced tumor uptake in 1 patient with cholangiocarcinoma stage II. In 2 patients with gallbladder carcinoma stage IV, neither 111In-cG250 nor 131I-cG250 showed targeting of known tumor lesions. Immunohistochemical analysis demonstrated CAIX expression in all 3 cases. There were no adverse events related to radiolabeled cG250 administration. CONCLUSIONS: 111In- or 131I-labeled cG250 is not suitable for biliary cancer targeting. Therefore, there is no basis to develop radioimmunotherapy based on radiolabeled cG250 in biliary cancer.

Scintigraphic imaging of P-glycoprotein expression with a radiolabelled antibody.

PURPOSE: P-glycoprotein (P-gp) is a membrane efflux pump protein that is involved in multidrug resistance (MDR). Tumour cells with high P-gp expression show poor response to cancer treatment with several chemotherapeutics. In vivo targeting and visualisation of P-gp expression would allow MDR to be evaluated non-invasively prior to treatment. The aim of this study was to investigate the feasibility of visualising P-gp expression in tumours using a monoclonal anti-P-gp antibody, 15D3. METHODS: Nude BALB/c mice with subcutaneously growing human uterine sarcoma cell tumours with either high (MES-SA/Dx5 1977) or low (MES-SA 1976) P-gp expression were used. When tumours were 0.2-0.4 g, mice received (131)I-15D3 or (111)In-DTPA-15D3 monoclonal anti-P-gp antibody intravenously. Images were acquired up to 3 days p.i. and radioactivity concentration in various tissues was determined after euthanisation of the animals. RESULTS: The images demonstrated that radioactivity accumulated to a higher concentration in high P-gp expressing tumours than in the low P-gp expressing MES-SA 1976 tumour. Furthermore, visualisation of the P-gp expressing tumours was superior with (111)In-DTPA-15D3 than with (131)I-15D3. After injection of (111)In-DTPA-15D3, the high P-gp expressing MES-SA/Dx5 1977 tumours were clearly visualised at 3 days p.i. The biodistribution data indicated that radioactivity concentration in the high P-gp expressing tumours was higher than in the tumours with low P-gp expression (20.78+/-1.42 %ID/g for MES-SA/Dx5 1977 tumours and 8.39+/-3.78 %ID/g for MES-SA 1976 tumours for (111)In-DTPA-15D3). CONCLUSION: The (111)In-labelled monoclonal anti-P-gp antibody clearly visualised P-gp expression in a human uterine sarcoma tumour in nude mice.

Effects of hyperoxygenation on FDG-uptake in head-and-neck cancer.

PURPOSE: Tumor hyperoxygenation results in high response rates to ARCON (accelerated radiotherapy with carbogen and nicotinamide). The effect of hyperoxygenation on tumor metabolism using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) was investigated. METHODS: Within one week, FDG-PET was performed without and with hyperoxygenation by carbogen breathing and/or nicotinamide administration in 22 patients, eligible for ARCON for head-and-neck cancer. Maximum standardized uptake values (SUV(max)) in both scans and the relative change were calculated in the primary tumor and in normal muscle. RESULTS: Alteration of the tumor oxygenation state induced profound, but variable, metabolic changes (median DeltaSUV(max) -4%; range -61% to +30%). Metabolism in normal muscle was not affected. In three patients who did not achieve local tumor control, the SUV(max) after hyperoxygenation differed less than 5% change as compared to baseline, whereas 13 of the 16 patients with local tumor control showed a larger difference (p<0.05). CONCLUSION: Given the heterogeneous response pattern of nicotinamide and carbogen on FDG-uptake in head-and-neck carcinoma, the prognostic significance of semiquantitative FDG-PET before and after hyperoxygenation remains uncertain and requires confirmation in larger clinical studies before introducing the procedure as a predictive tool for oxygenation modifying treatments.