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Purpose: We quantified the performance of time-domain imaging (TDI) and spectral imaging (SI) for fluorescence imaging of quantum dots (QDs) in three distinct imaging instruments: eXplore Optix (TDI, Advanced Research Technologies Inc.), Maestro (SI, CRi Inc.), and IVIS-Spectrum (SI, Caliper Life Sciences Inc.)., Procedure: The instruments were compared for their sensitivity in phantoms and living mice, multiplexing capabilities (ability to resolve the signal of one QD type in the presence of another), and the dependence of contrast and spatial resolution as a function of depth., Results: In phantoms, eXplore Optix had an order of magnitude better sensitivity compared to the SI systems, detecting QD concentrations of ~40 pM in vitro. Maestro was the best instrument for multiplexing QDs. Reduction of contrast and resolution as a function of depth was smallest with eXplore Optix for depth of 2-6 mm, while other depths gave comparable results in all systems. Sensitivity experiments in living mice showed that the eXplore Optix and Maestro systems outperformed the IVIS-Spectrum., Conclusion: TDI was found to be an order of magnitude more sensitive than SI at the expense of speed and very limited multiplexing capabilities. For deep tissue QD imaging, TDI is most applicable for depths between 2 and 6 mm, as its contrast and resolution degrade the least at these depths.

Purpose: ReO(4)(-) has similar kinetics regarding the sodium iodide symporter (NIS) to I(-) and TcO(4)(-) in NIS-expressing tissue. We investigated the therapeutic potential of (186)ReO(4)(-) in NIS-transfected neuroendocrine tumour tissue., Methods: For experiments, the stably NIS-transfected pancreatic neuroendocrine cancer cell line Bon1C was used. NIS-mediated internalization and externalization experiments in vitro and a biodistribution study in nude mice bearing Bon1C xenografts were performed. A therapy study was also conducted consecutively in nude mice xenografted with Bon1C in which the mice were injected intravenously with Na(186)ReO(4)., Results: In vitro studies showed exponential internalization and efflux kinetics of (186)ReO(4)(-) in the cell line. The biodistribution study showed high uptake of (186)ReO(4)(-) in NIS-expressing tumours. Tumour growth inhibition was significant after injection of (186)ReO(4) in two groups of animals treated with activity levels below the determined maximum tolerable activity as compared to controls., Conclusion: These results indicate that the use of (186)ReO(4)(-) in the treatment of NIS-expressing neuroendocrine tumours is feasible and support the concept of using NIS as a therapeutic target for (186)ReO(4)(-).

This study evaluates the influence of particle size, PEGylation, and surface coating on the quantitative biodistribution of near-infrared-emitting quantum dots (QDs) in mice. Polymer- or peptide-coated 64Cu-labeled QDs 2 or 12 nm in diameter, with or without polyethylene glycol (PEG) of molecular weight 2000, are studied by serial micropositron emission tomography imaging and region-of-interest analysis, as well as transmission electron microscopy and inductively coupled plasma mass spectrometry. PEGylation and peptide coating slow QD uptake into the organs of the reticuloendothelial system (RES), liver and spleen, by a factor of 6-9 and 2-3, respectively. Small particles are in part renally excreted. Peptide-coated particles are cleared from liver faster than physical decay alone would suggest. Renal excretion of small QDs and slowing of RES clearance by PEGylation or peptide surface coating are encouraging steps toward the use of modified QDs for imaging living subjects.

Purpose: To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice., Materials and Methods: Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Lipid-shell perfluorocarbon-filled MBs, targeted to VEGFR2 via anti-VEGFR2 antibodies, were radiolabeled by conjugating the radiofluorination agent N-succinimidyl-4-[(18)F]fluorobenzoate (SFB) to the anti-VEGFR2 antibodies. These MBs were then injected intravenously into nude mice (n = 4) bearing angiosarcomas, and the whole-body biodistribution of these probes was assessed for 60 minutes by using dynamic micro-PET. Results were compared with ex vivo gamma counting (n = 6) and immunofluorescence staining (n = 6). Control studies in angiosarcoma-bearing mice were performed with injection of the radiolabeled antibodies alone (n = 3) or free SFB (n = 3). A mixed-effects regression of MB accumulation on fixed effects of time and tissue type (tumor or muscle) and random effect of animal was performed., Results: VEGFR2-targeted MBs rapidly cleared from the blood circulation (50% blood clearance after approximately 3.5 minutes) and accumulated in the liver (mean, 33.4% injected dose [ID]/g +/- 13.7 [standard deviation] at 60 minutes) and spleen (mean, 9.3% ID/g +/- 6.5 at 60 minutes) on the basis of micro-PET imaging. These findings were confirmed with ex vivo gamma counting. Uptake of targeted MBs was significantly higher (P < .0001) in tumor than in adjacent skeletal muscle tissue. Immunofluorescence staining demonstrated accumulation of the targeted MBs within hepatic Kupffer cells and splenic macrophages. Biodistribution of the radiolabeled antibodies and free SFB differed from the distribution of the targeted MBs., Conclusion: Dynamic micro-PET allows assessment of in vivo biodistribution of VEGFR2-targeted MBs., ((c) RSNA, 2008.)

Single-walled carbon nanotubes are currently under evaluation in biomedical applications, including in vivo delivery of drugs, proteins, peptides and nucleic acids (for gene transfer or gene silencing), in vivo tumour imaging and tumour targeting of single-walled carbon nanotubes as an anti-neoplastic treatment. However, concerns about the potential toxicity of single-walled carbon nanotubes have been raised. Here we examine the acute and chronic toxicity of functionalized single-walled carbon nanotubes when injected into the bloodstream of mice. Survival, clinical and laboratory parameters reveal no evidence of toxicity over 4 months. Upon killing, careful necropsy and tissue histology show age-related changes only. Histology and Raman microscopic mapping demonstrate that functionalized single-walled carbon nanotubes persisted within liver and spleen macrophages for 4 months without apparent toxicity. Although this is a preliminary study with a small group of animals, our results encourage further confirmation studies with larger groups of animals.

Unlabelled: This study evaluates the quantitative biodistribution of commercially available CdSe quantum dots (QD) in mice., Methods: (64)Cu-Labeled 800- or 525-nm emission wavelength QD (21- or 12-nm diameter), with or without 2,000 MW (molecular weight) polyethylene glycol (PEG), were injected intravenously into mice (5.55 MBq/25 pmol QD) and studied using well counting or by serial microPET and region-of-interest analysis., Results: Both methods show rapid uptake by the liver (27.4-38.9 %ID/g) (%ID/g is percentage injected dose per gram tissue) and spleen (8.0-12.4 %ID/g). Size has no influence on biodistribution within the range tested here. Pegylated QD have slightly slower uptake into liver and spleen (6 vs. 2 min) and show additional low-level bone uptake (6.5-6.9 %ID/g). No evidence of clearance from these organs was observed., Conclusion: Rapid reticuloendothelial system clearance of QD will require modification of QD for optimal utility in imaging living subjects. Formal quantitative biodistribution/imaging studies will be helpful in studying many types of nanoparticles, including quantum dots.

Purpose: There is growing interest in the human sodium/iodide symporter (NIS) gene both as a molecular imaging reporter gene and as a therapeutic gene. Here, we show the feasibility of radioisotope therapy of neuroendocrine tumors. As a separate application of NIS gene transfer, we image NIS-expressing tumors with pinhole SPECT in living subjects., Methods: Biodistribution studies and in vivo therapy experiments were performed in nude mice carrying stably NIS-expressing neuroendocrine tumor xenografts following i.v. injection of (131)I and (99m)Tc pertechnetate. To show the usefulness of NIS as an imaging reporter gene, (99m)Tc pertechnetate uptake was imaged in vivo using a clinical gamma camera in combination with a custom-made single pinhole collimator, followed by SPECT/small animal MRI data coregistration., Results: NIS-expressing neuroendocrine tumors strongly accumulated (131)I and (99m)Tc pertechnetate, as did thyroid, stomach, and salivary gland. The volume of NIS-expressing neuroendocrine tumors decreased significantly after therapeutic administration of (131)I or (99m)Tc pertechnetate, whereas control tumors continued to grow. NIS-mediated uptake of (99m)Tc pertechnetate could be imaged in vivo at high resolution with a clinical gamma camera equipped with a custom-made single pinhole collimator. High-resolution functional and morphologic information could be combined in a single three-dimensional data set by coregistration of SPECT and small animal MRI data. Lastly, we demonstrated a therapeutic effect of (99m)Tc pertechnetate on NIS-expressing neuroendocrine tumors in cell culture and, for the first time, in vivo, thought to be due to emitted Auger and conversion electrons., Conclusions: NIS-expressing neuroendocrine tumors efficiently concentrate radioisotopes, allowing for in vivo high-resolution small animal SPECT imaging as well as rendering possible successful radioisotope therapy of neuroendocrine tumors.

Purpose: Evaluation of selective killing of Herpes Simplex Virus 1 thymidine kinase (HSV1-tk) expressing tumors by radiolabeled (131)I-fialuridine (FIAU), and of synergy between (131)I-FIAU and Ganciclovir (GCV)., Procedures: HSV1-tk-expressing cell lines and parental cell lines were exposed to (131)I-FIAU alone, GCV alone, or combinations. Activity and concentration were varied widely, concurrent and sequential administrations tested, and dose rate effects were studied., Results: HSV1-tk-expressing cells accumulated up to 15.7-fold more (131)I-FIAU, were growth inhibited by 2 muCi/ml, or 5 muCi/ml (131)I-FIAU, and were inhibited by two log orders lower concentrations of GCV than parental cells. However, no synergy or additive effect was observed. Dose rate variations, or sequential treatment, did not alter outcome., Conclusion: Radioisotope therapy of HSV1-tk-expressing tumor cells with (131)I-FIAU is reported for the first time. Lack of synergy between (131)I-FIAU and GCV does not warrant further investigation of combination treatment with the two agents.

Gastrin receptor scintigraphy (GRS) is a new imaging method primarily developed for the detection of metastases of medullary thyroid carcinoma (MTC). As gastrin-binding CCK(2) receptors are also expressed on a variety of other neuroendocrine tumours (NET), we compared GRS to somatostatin receptor scintigraphy (SRS) in patients with NET. SRS and GRS were performed within 21 days in a series of 60 consecutive patients with NET. GRS was directly compared with SRS. If lesions were visible on GRS but not detectable by SRS, other imaging modalities (MRI, CT) and follow-up were used for verification. Of the 60 evaluable patients, 51 had carcinoid tumours, 3 gastrinomas, 2 glucagonomas, 1 insulinoma and 3 paragangliomas. The overall tumour-detection rate was 73.7% for GRS and 82.1% for SRS. In the 11 patients with negative SRS, GRS was positive in 6 (54.5%). Based on the number of tumour sites detected and the degree of uptake, GRS performed better than SRS in 13 patients (21.7%), equivalent images were obtained in 18 cases (30.0%) and SRS performed better in 24 (40.0%) cases. In six of the SRS positive patients, 18 additional sites of tumour involvement could be detected. Overall, GRS detected additional tumour sites in 20% of the patients. Localisation of the primary tumours or their functional status had no influence on the outcome of imaging. GRS should be performed in selected patients as it may provide additional information in patients with NET with equivocal or absent somatostatin uptake.

Purpose: This work investigated whether fLuc-catalyzed oxidation of D-luciferin generates sufficient light to induce photodynamic toxicity in cancer cells., Procedures: Light emission was assessed via cooled CCD (charge-coupled device) camera. Parental and fLuc expressing cancer cells were exposed to subtoxic concentrations of photosensitizers (Rose Bengal or hypericin) and D-luciferin, sunlight, or lamplight. Toxicity was assessed by MTT assay., Results: fLuc expressing cells emitted up to 500-fold higher levels of photons than parental cell lines. Although exposure to photosensitizer and sunlight reduced survival of various cell lines, survival of fLuc expressing cells incubated with photosensitizer and D-luciferin, or photosensitizer and lamplight, did not differ significantly from parental or untreated cells., Conclusions: Contesting recent reports, fLuc bioluminescence does not generate sufficient photons to induce Rose Bengal or hypericin photodynamic toxicity in a range of malignant and nonmalignant cell lines, and is not suitable as a generalizable approach to antineoplastic therapy.

Bone metastases from a vulvar carcinoma are exceptionally rare with only five reported cases in the literature. We report on a patient who was initially treated with radical vulvectomy and bilateral inguinal lymphadenectomy for a vulvar cancer (pT2, pN2 (6/37), M0; G2). Due to a positive nodal status, adjuvant radiation of the vulva and the pelvis was performed additionally. The patient presented 4 months after initial therapy with severe pain in the right humeral shaft due to a pathologic fracture based on an osteoclastic metastasis. During osteosynthetic stabilization histologic and immunohistochemical stain gave evidence of a metastasis of the known vulvar carcinoma. Bone scan showed enhancements in both humeral heads as well as the right distal femur, whereas plain radiographs confirmed further metastases in all suspected areas. In conclusion, bone metastases should be considered in the differential diagnoses of unclear osseous pain in women with a history of vulvar cancer. Immunohistochemical examinations might be important to depict the epithelial character of the tissue and allude to the metastatic nature of such rare lesions. The atypical location should alert the physician to suspect distant metastasis, rather than locoregional disease.

There is a considerable discrepancy in the literature concerning the sensitivity of parathyroid scintigraphy (PS) with 99mTc-MIBI. We therefore analyzed our own data and compared them to the literature in a metaanalysis. All patients who received 99mTc -MIBI scintigraphy and subsequent surgery in our department for the detection of enlarged parathyroid glands in primary (pHPT) or secondary (sHPT) hyperparathyroidism between 1991 and 1999 were included in our retrospective analysis. The results of surgery served as the gold standard. For a true positive result, the scintigraphy had to predict the exact location of parathyroid adenoma (PA) or parathyroid hyperplasia (PH). We then compared these data to the results of a nonstatistical systematic metaanalysis of the literature. Patients (178) underwent PS between 1991 and 1999; 139 were operated on and included in this study. Of these, 109 had pHPT and 30 had sHPT. The sensitivity and specificity of the PS were found to be 45%/94% for pHPT and 39%/40% for sHPT. Fifty-two studies concerning PS were included in the metaanalysis. Sensitivities reported varied from 39% to >90%. Consideration of the different possible techniques used for PS could not explain these discrepancies. Our data show that the sensitivity of PS in clinical routine may be lower than expected from the literature. Our data are consistent with other studies and with partially unpublished clinical observations from other university hospitals. We believe that a well-designed and properly conducted prospective study is necessary to evaluate the reasons for the differences observed.

Calculation of iodine-131 activities for radioiodine treatment (RIT) in patients with disseminated thyroid autonomy may be difficult because of uncertainties in the determination of the autonomous volume (vol(aut)). The algorithm established by Emrich is used for calculation of the vol(aut) based on the TcTUs (technetium thyroid uptake under TSH suppression) (vol(aut)= 5xTcTUs+0.6). Clinical experience using this approach has shown that there is a negative correlation between increasing TcTUs and the results of RIT. Our aim was to identify the reasons for this observation as well as to assess the relation between TcTUs and sonographic vol(aut). Furthermore, we intended to find an alternative algorithm for the TcTUs-based calculation of the vol(aut). Data from 100 patients with unifocal autonomy who met strict inclusion criteria were used to evaluate the correlation between TcTUs and sonographic vol(aut). Using Marinelli's algorithm, we calculated the therapeutic activities for a standardised patient at a target dose of 300 Gy. The vol(aut) was determined based on the TcTUs using the four published algorithms [Emrich 1993 (vol(aut)= 5xTcTUs+0.6), Kreisig 1992 (vol(aut)=10xTcTUs-9.3), Joseph 1977 (vol(aut)=8.33xTcTUs-6.67) and 1994 (vol(aut)=2.88xTcTUs+0.09)]. We then compared the results of the calculation of therapeutic activities obtained using Emrich's algorithm (with known success rates) with those obtained by the other algorithms in order to determine which algorithm would lead to better results in RIT. Only a weak correlation was found between the TcTUs and the sonographic vol(aut) ( r(2)=0.39). The calculated therapeutic activities of (131)I were similar for all algorithms at a TcTUs of around 2% but Joseph's (1977) and Kreisig's (1992) algorithms resulted in clearly higher activities than Emrich's algorithm at a TcTUs above 2%. The need for target doses to increase with TcTUs in RIT may be overcome by the use of adequate algorithms for determination of the vol(aut). The algorithm published by Joseph and co-workers in 1977 probably offers the most reliable approach to the TcTUs-based calculation of vol(aut) in RIT. In contrast to the other algorithms, it is based on autoradiographic planimetric data. Thus, it takes into account the polyclonal origin of thyroid nodules as well as the presence of regressive or cystic changes. The well-established algorithm of Emrich underestimates the true vol(aut), which explains the decreasing success of RIT with increasing TcTUs.

Purpose: The aim of the current study was to determine the overall diagnostic accuracy of Tc-99m-labeled antigranulocyte monoclonal antibody Fab' fragments (LeukoScan) for the routine detection of bone and soft tissue infections in a retrospective evaluation., Patients and Methods: 138 patients (63 men, 75 women; mean age, 58.29 +/- 25.38 years) with fever of unknown origin and possible endocarditis (n = 59), infection of arthroplastic joints (n = 20), arthritis (n = 16), peripheral (n = 15) and central bone infections (n = 14), soft tissue infection (n = 6), appendicitis (n = 4), pericarditis (n = 2), or vascular graft infection (n = 2) underwent imaging after injection of 555 to 925 MBq (15 to 25 mCi) Tc-99m-labeled antigranulocyte monoclonal antibody Fab' fragments (LeukoScan)., Results: True-positive results were found in 63 of 81 lesions. The overall sensitivity and specificity were 76% and 84%, respectively. In arthritis, seven of seven foci could be detected, whereas false-negative results were found in infections of the femoral bone in three of nine lesions and in periprosthetic infections of long bones in three of eight lesions. Good results were found in five of six soft-tissue infections, in four of six patients with endocarditis, in three of four atypical cases of appendicitis, in two of two infected vascular grafts, and in one of one patient with pericarditis. Subacute and chronic infections of the spine always showed photopenic areas in eight of eight patients. If photopenic lesions were included as diagnostic criteria, the sensitivity and specificity were 88% and 67%, respectively., Conclusions: Tc-99m-labeled antigranulocyte monoclonal antibody Fab' fragments can be used for imaging acute infections of peripheral bones and soft tissues. False-negative results are likely in patients with chronic infections. Sensitivity can be increased while decreasing specificity by including photopenic lesions in the spine as diagnostic criteria for localizing disease.

This study evaluates the possibility of treating Bon1 and QGP pancreatic neuroendocrine tumor cells with radioactive iodide ((131)I) after stable transfection with the thyroid sodium iodide symporter (NIS). NIS expression was driven either by the strong viral cytomegalovirus promoter or by the tissue-specific chromogranin A promoter. Using either approach, NIS expression was confirmed by reverse transcription-PCR and Western blotting. Uptake of radioactive iodide was increased approximately 20-fold by chromogranin A promoter-driven NIS expression and approximately 50-fold by cytomegalovirus promoter-driven NIS expression. Maximal uptake was reached within 15 min in QGP cells and 30 min in Bon1 cells. Effective half-life was 5 min in QGP and 30 min in Bon1 cells. No evidence of organification was detected by high-performance liquid chromatography and gel filtration chromatography. (131)I was a highly effective treatment in NIS-expressing QGP and Bon1 cells, reducing clone formation by 99.83 and 98.75%, respectively, in the in vitro clonogenic assay. In contrast, clone formation was not reduced in QGP and Bon1 cells without NIS expression after incubation with the same activity concentration of (131)I as compared with mock treated cells. Absorbed doses to QGP and Bon1 cells are up to 150 and 30 Gy, respectively. In addition, a direct cytotoxic effect of radioiodide was demonstrated in NIS-expressing Bon1 cells after (131)I incubation. In conclusion, radioiodide treatment after NIS gene transfer appears to be a promising novel approach in the therapy of neuroendocrine tumors if its highly encouraging in vitro effectiveness can be transferred to the in vivo situation.

The recent cloning and molecular characterization of the sodium iodide-symporter (NIS) has inspired novel approaches to the diagnosis and treatment of thyroidal and nonthyroidal malignancies. This article briefly reviews the physiologic regulation of NIS expression by cytokines, the expression in benign and malignant thyroidal diseases, and the expression in extrathyroidal tissues. Current concepts for NIS-based cancer therapy in thyroidal and extrathyroidal tumors are presented. The recent discovery of NIS expression in a majority of breast cancers as well as its promising application for prostate cancer imply potential applications in diagnostic imaging and radioiodine anticancer therapy for these highly common and lethal malignancies.