Annals of Nuclear Medicine (v.26, #3)

Bone is one of the organs to which cancer metastasizes most frequently. However, it is not a vital organ, therefore, survival after the occurrence of osseous metastasis is relatively favorable. Improvements of medical treatment bring prolonged survival to patients with osseous metastases. But this makes us to recognize the importance of quality of life (QOL) due to several factors, including pain. It is important for oncologists to know how to deal with such painful osseous metastases, as pain relief may enable patients to live their remaining lives to the fullest. Strontium-89 (89Sr) has been used worldwide as in Japan, while being reported to have positive effects on pain relief and QOL improvement in patients with osseous metastases. This review paper is aimed to present not only the history, roles, and medical characters of 89Sr, but also new aspects, such as how to use bone turnover markers, which location of osseous metastases is suitable for effective use of 89Sr.
Keywords: Strontium-89; Pain; Osseous metastases

FDG-PET performed concurrently with initial I-131 ablation for differentiated thyroid cancer by Shingo Iwano; Katsuhiko Kato; Shinji Ito; Kenichi Tsuchiya; Shinji Naganawa (207-213).
Differentiated thyroid cancers (DTCs) are commonly treated by total thyroidectomy followed by I-131 radioiodine ablation to eradicate any residual thyroid tissue and to detect any metastatic lesions on post-treatment whole body scans (TxWBS). However, some DTCs do not trap iodine, resulting in negative whole body scanning. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has proven to be a valuable diagnostic technique for detecting many types of malignant tumors and metastases. The purpose of this study was to evaluate FDG-PET performed concurrently with initial I-131 ablation for its ability to detect lymph node metastasis and for its role in the management of DTC patients.A total of 54 patients (16 males and 38 females; median age = 50 years) with histologically proven DTC underwent both FDG-PET and subsequent I-131 ablation. A dose of 3.7 GBq I-131 was administered to 51 patients, 2.96 GBq was administered to 1 patient, and 2.22 GBq was administered to 2 patients. FDG-PET or PET/CT was performed 3–4 days prior to ablation. TxWBS was conducted 1 week after therapy. FDG-PET scans and TxWBS were interpreted by consensus of 2 experienced radiologists. Serum thyroglobulin (Tg) levels at 3–6 months after ablation were compared between PET-positive and PET-negative patients.FDG-PET was positive in 25 sites (thyroid bed: n = 9; cervical lymph nodes: n = 12; mediastinal lymph nodes: n = 3; and axillary lymph nodes: n = 1) of 18 patients (33%). Only 5 of 16 lymph nodes (31%) that were PET-positive were also positive on TxWBS. The success rate of Tg-negative after ablation was significantly lower for patients with PET-positive scans than for those with PET-negative scans (p = 0.026).FDG-PET performed concurrently with I-131 ablation can detect lymph node metastases in which radioiodine does not accumulate and may influence the management and treatment options for DTC patients.
Keywords: Thyroid cancer; Radioiodine therapy; Whole body scan; Fluorine-18-fluorodeoxyglucose; Positron emission tomography

In a typical single photon emission computed tomography (SPECT) system, intrinsic spatial resolution depends on the accuracy of the identification of an interacting point, which is dominated by propagation of the scintillation photons in the detector block. This study was intended to establish a Monte Carlo simulation-based evaluation tool taking into account the propagation of scintillation photons to estimate the intrinsic spatial and energy resolutions of the position-sensitive scintillator block in a SPECT detector.We employed Geant4 Monte Carlo simulation library which incorporated the optical photon processes for two different designs of the position-sensitive scintillator blocks. The validation of the simulation code was performed for a monolithic NaI(Tl) scintillator (251 × 147 × 6.4 mm3) coupled to 15 flat-panel type multi-anode photo multiplier tubes (PMT) (H8500: Hamamatsu) and results were compared with those obtained experimentally. The code was then applied to a LaBr3(Ce) scintillator of 120 mm square with varied thicknesses for designing high-resolution detector.The simulation resulted in 2.6 mm full width at half maximum (FWHM) of spatial resolution and 9.0% FWHM of energy resolution for the NaI(Tl)-based detector, which were in a good agreement of the experimental results, i.e., 2.7 mm and 10%, respectively. These findings suggest that Geant4 simulation including optical photon processes enables to predict the spatial and energy resolutions of a SPECT detector block accurately. The simulation also demonstrated that 2 mm spatial resolution can be obtained for a 6 mm thickness of the LaBr3(Ce), which is a significant improvement in performance as compared to existing gamma camera system that employs the scintillation detector fitted with PMTs.The Monte Carlo simulation-based evaluation tool was established to estimate the intrinsic spatial and energy resolutions of SPECT detector with position sensitive PMTs. This simulation may be useful to provide an optimal design of a SPECT detector without physical experiments.
Keywords: LaBr3(Ce); Monte Carlo simulation; Geant4; SPECT; Scintillation photon

Intratumoral heterogeneity of F-18 FDG uptake differentiates between gastrointestinal stromal tumors and abdominal malignant lymphomas on PET/CT by Tadashi Watabe; Mitsuaki Tatsumi; Hiroshi Watabe; Kayako Isohashi; Hiroki Kato; Masahiro Yanagawa; Eku Shimosegawa; Jun Hatazawa (222-227).
Gastrointestinal stromal tumors (GISTs) and malignant lymphomas (MLs) in the abdomen are often observed as tumors of unknown origin on F-18 FDG PET/CT. The purpose of this study was to evaluate the intratumoral metabolic heterogeneity of F-18 FDG uptake on PET to determine if it might be helpful to discriminate between these tumors.The F-18 FDG PET/CT findings of 21 large abdominal tumors were retrospectively evaluated (9 GISTs and 12 MLs). Intratumoral heterogeneity was evaluated by visual scoring (visual score: 0, homogeneous; 1, slightly heterogeneous; 2, moderately heterogeneous; 3, highly heterogeneous) and by the cumulative standardized uptake value (SUV) histograms on transaxial PET images at the maximal cross-sectional tumor diameter. Percent tumor areas above a threshold from 0 to 100% of the maximum SUV were plotted and the area under curve of the cumulative SUV histograms (AUC-CSH) was used as a heterogeneity index, where lower values corresponded with increased heterogeneity. Correlation between the visual score and the AUC-CSH was investigated by the Spearman’s rank test.GISTs exhibited heterogeneous uptake of F-18 FDG, whereas MLs showed rather homogeneous uptake on visual analysis (visual score: 2.67 ± 0.50 and 0.58 ± 0.79, respectively; p < 0.001). The AUC-CSH was significantly lower for the GISTs than for the MLs (0.41 ± 0.14 and 0.64 ± 0.08, respectively; p < 0.001). Significant correlations were observed between the visual score and the AUC-CSH (ρ = −0.866, p < 0.001).GISTs exhibited significantly heterogeneous intratumoral tracer uptake as compared with the MLs. Evaluation of the intratumoral heterogeneity of F-18 FDG uptake may help in the discrimination between these tumors.
Keywords: F-18 FDG PET; Intratumoral heterogeneity; Gastrointestinal stromal tumor; Malignant lymphoma; Cumulative standardized uptake value histograms

Bone marrow stem cell adherence into old anterior myocardial infarction: a scintigraphic study using Tl-201 and Tc-99m-HMPAO by Nikolaos Kollaros; Athanasios Theodorakos; Athanasios Manginas; Elpida Kitziri; Athanasios Katsikis; Dennis Cokkinos; Maria Koutelou (228-233).
The precise localization of bone marrow stem cells (SCs) into the necrotic tissue after intracoronary infusion (ICI) may be important for the therapeutic outcome. This study aims to examine the correlation between Tl-201 and Tc-99m-hexa-methyl-propylene-amine-oxime (HMPAO) images.Thirteen patients, aged 36–62 years, with an old, nonviable, anterior myocardial infarction (MI) and reduced myocardial contractility (LVEF <40%), underwent ICI of selected CD133+ and CD133negCD34+ SCs. One hour after the ICI, SPECT imaging with Tc-99m-HMPAO was performed in all patients and the acquired images were compared with the images obtained during the initial imaging for demonstration of viability (myocardial perfusion imaging with pharmacologic stress and Tl-201). Furthermore, two fused bull’s eye images of Tc-99m-HMPAO and Tl-201 rest reinjection were created in six patients and regions of interest were set on Tl-201 and Tc-99m-HMPAO bull’s eye images.The comparison of the two sets of images revealed an intense accumulation of the SCs in the infarcted area with absence of viability as assessed by Tl-201 reinjection images. In the subset of patients in whom fused bull’s eye images were produced, the comparison demonstrated that the percentage of the infarcted area with SCs’ adherence was 83.2 ± 17%.Tl-201 images are complementary with the respective Tc-99m-HMPAO ones, revealing a precise localization of SCs in the infarcted area. Tc-99m-HMPAO labeling of SCs is a reliable method for cell monitoring after ICI in nonviable myocardium after an anterior MI.
Keywords: Tc-99m-HMPAO; TL-201; Stem cells; Myocardial infarction; Cell monitoring

Interobserver variability, and visual and quantitative parameters of 123I-FP-CIT SPECT (DaTSCAN) studies by Nikolaos Papathanasiou; Phivi Rondogianni; Panagiota Chroni; Marios Themistocleous; Efstathios Boviatsis; Xanthi Pedeli; Damianos Sakas; Ioannis Datseris (234-240).
To evaluate the degree of interobserver agreement in the visual interpretation of 123I-FP-CIT studies and to investigate for potential associations between visual and semi-quantitative parameters.Eighty-nine 123I-FP-CIT studies were blindly reviewed by 3 independent observers: a consultant, a resident doctor and a radiographer. They classified every study as either “normal” or “abnormal” and assigned visual 123I-FP-CIT uptake scores (2: normal, 1: reduced and 0: no uptake) in basal ganglia nuclei (right and left putamina and caudate nuclei) on every scan. Striatal 123I-FP-CIT binding ratios were calculated using crescent-ROI software. The interobserver agreement for the interpretation of studies and for visual score assignment was evaluated by means of κ statistics. We investigated for associations of binding ratios with visual scores and clinical parameters; patients’ clinical diagnoses served as the reference standard.There was excellent interobserver agreement (κ 0.89–0.93) in classifying studies as “normal” or “abnormal” and fine agreement in assignment of visual scores (κ 0.71–0.80 for putamina and 0.50–0.79 for caudate nuclei). Nuclei with scores of 1 and 0 showed significantly reduced binding ratios (about 30 and 50%, respectively) compared with the nuclei scored as 2. ROC analysis indicated the optimal cutoff point of striatal binding ratio at 3.8 (sensitivity 98.5%, specificity 95%) for the detection of parkinsonian syndromes. Striatal binding ratios were negatively associated with age in normal subjects and disease duration in Parkinson’s disease patients.Visual interpretation of 123I-FP-CIT studies showed very good interobserver agreement. We found significant associations among visual, semi-quantitative and clinical parameters.
Keywords: ¹²³I-FP-CIT; DaTSCAN; Parkinson’s disease; Interobserver variability

Impact of CT attenuation correction by SPECT/CT in brain perfusion images by Kazunari Ishii; Kohei Hanaoka; Masahiro Okada; Seishi Kumano; Yoshihiro Komeya; Norio Tsuchiya; Makoto Hosono; Takamichi Murakami (241-247).
The aim of this study was to elucidate the regional differences between brain perfusion single photon emission computed tomography (SPECT) images reconstructed with a uniform attenuation correction using Chang’s method (AC-Chang) and a non-uniform attenuation correction with CT using SPECT/CT (AC-CT).SPECT images of a phantom with and without head holder were obtained, and reconstructed images of AC-Chang and AC-CT were compared. Twenty-eight consecutive patients with brain disease examined by SPECT/CT brain perfusion imaging were selected, and images were reconstructed with AC-Chang and AC-CT. The AC-Chang and AC-CT reconstructed images were then compared by voxel-based analysis using three-dimensional stereotactic surface projections.Counts in the frontal area of the AC-Chang phantom image with head holder were higher than those in the posterior area. Counts in the frontal area of the AC-Chang clinical images were significantly higher than those in the AC-CT images, while the counts in the margin of the frontal lobe and posterior margin of the parietal, occipital cortices and cerebellum of the AC-Chang images were significantly lower. Relative frontal perfusion was 5.0% higher and relative cerebellar perfusion was 4.6% lower in the AC-Chang images relative to the AC-CT images, on average.We demonstrated the frontal dominant hyper-perfusion and parieto-occipital and cerebellar hypo-perfusion in brain SPECT images reconstructed with AC-Chang compared to those reconstructed with AC-CT. We suggest that to obtain an accurate attenuation-corrected brain perfusion SPECT image, attenuation correction by Chang’s method is inadequate.
Keywords: SPECT/CT; Brain perfusion; Attenuation correction; Chang’s method

Axillary lymph node accumulation on FDG-PET/CT after influenza vaccination by Norihisa Shirone; Takayuki Shinkai; Tomohiko Yamane; Fumiaki Uto; Hitoshi Yoshimura; Hiroyuki Tamai; Teruhiko Imai; Makoto Inoue; Satoru Kitano; Kimihiko Kichikawa; Masatoshi Hasegawa (248-252).
2-[18F]fluoro-2-deoxy-d-glucose (FDG) is known to accumulate in benign conditions such as infection and inflammation as well as in malignancy. Vaccination may cause transient inflammation of lymph nodes, which may induce false-positive findings on FDG-positron emission tomography (PET) imaging. This study investigated the influence of influenza vaccination on FDG-PET/CT imaging in normal subjects.Between November 2008 and March 2009, a total of 172 examinees underwent FDG-PET/CT during an annual cancer-screening program at our hospital, 83 of whom had a history of recent non-adjuvanted seasonal influenza vaccination. They were asked the date and injection site of the vaccination. Examinees were divided into 2 groups based on the interval after vaccination using a cutoff value of 7 days (1 week). Two double board-certified nuclear medicine physicians and radiologists visually interpreted the FDG-PET/CT images with reference to PET/CT fusion and CT images and checked the location and the number of abnormal accumulations by consensus reading.Intervals between vaccination and FDG-PET were less than 7 days in 5 examinees, and 7 days or more in 78 examinees. Unexpected accumulations were visualized in 4 examinees in the axilla and medial upper arm, and all of them belonged to the group who underwent vaccination less than 7 days previously. In the second group there was no abnormal FDG accumulation.Recent influenza vaccination before FDG-PET/CT examination may cause ipsilateral axillary lymph node accumulations, especially within several days after vaccination. Questionnaires about vaccination can help to avoid false interpretation of FDG avid axillary lymph nodes.
Keywords: FDG-PET/CT; Influenza vaccination; False positive; Cancer screening

Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with 99mTc-DTPA-glipizide by Chang-Sok Oh; Saady Kohanim; Fan-Lin Kong; Ho-Chun Song; Nathan Huynh; Richard Mendez; Mithu Chanda; E. Edmund Kim; David J. Yang (253-261).
This study was aimed to assess pancreas beta cell activity using 99mTc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated.DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30–120 min after injection of 99mTc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given 99mTc-DTPA. To demonstrate pancreas beta cell uptake of 99mTc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, i.v.) and the images were acquired at immediately—65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h.The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. 99mTc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas 99mTc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with 99mTc-DTPA-GLP in normal rat, however, 99mTc-DTPA has poor uptake suggesting the specificity of 99mTc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug.It is feasible to use 99mTc-DTPA-GLP to assess pancreas beta cell receptor recognition. 99mTc-DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors.
Keywords: 99mTc-DTPA-glipizide; Sulfonylurea receptor; Imaging; Pancreas

Relation between FDG uptake and apparent diffusion coefficients in glioma and malignant lymphoma by Nobuyoshi Matsushima; Masayuki Maeda; Maki Umino; Naohisa Suzawa; Tomomi Yamada; Kan Takeda (262-271).
This study evaluates the relation between 2-deoxy-2-[18F]fluoro-d-glucose (FDG) uptake using positron emission tomography/CT and the apparent diffusion coefficient (ADC) in patients with glioma and malignant lymphoma.For 36 patients (30 with glioma and 6 with malignant lymphoma), the standardized uptake value (SUV) ratio was calculated to assess the FDG uptake. Pearson’s correlation analysis was used to assess the relation between the SUV ratio and the ADC value: those of low-grade glioma and high-grade glioma were compared, as were those of glioblastoma and malignant lymphoma.Inverse correlation between the SUV ratio and the minimum ADC was found for all cases (P < 0.0001, r = 0.68) and for glioma cases (P < 0.0001, r = 0.67). High-grade gliomas showed a significantly higher SUV ratio than low-grade gliomas did (P < 0.0001); they also showed significantly lower minimum ADC than low-grade gliomas did (P < 0.001). Cut-off values used for the SUV ratio of 0.9 and for the minimum ADC of 0.99 × 10−3 mm2/s were used to differentiate high-grade from low-grade gliomas, with high accuracy. Malignant lymphoma showed a significantly higher SUV ratio than glioblastoma (P < 0.0001). No significant difference in the ADC value was found between glioblastoma and malignant lymphoma (the minimum ADC: P = 0.13, the mean ADC: P = 0.084, respectively).An inverse correlation was found between the SUV ratio and the minimum ADC in glioma and malignant lymphoma. The SUV ratio and the minimum ADC are useful to evaluate the grading of gliomas. The SUV ratio might be more useful for differentiating malignant lymphoma from glioblastoma than the ADC value is.
Keywords: Glioma; Lymphoma; ADC; SUV; FDG-PET/CT

In vivo imaging of radiation-induced tissue apoptosis by 99mTc(I)-his6-annexin A5 by Kun-Ju Lin; Chun-Chung Wu; Yi-Hsin Pan; Fang-Hsing Chen; Sheng-Yung Fu; Chi-Shiun Chiang; Ji-Hong Hong; Jem-Mau Lo (272-280).
A recombinant annexin A5 with the N-terminal extension of six histidine residues was labeled with 99mTc(I)-tricarbonyl ion to produce the 99mTc-labeled annexin A5, referred to 99mTc(I)-his6-annexin A5. We have explored the agent as an effective imaging probe for in vivo detecting the apoptosis of internal tissue subjected with high radiation doses in a γ-irradiated mouse model.[99mTc(CO)3(OH2)3]+ was prepared and taken to directly label his6-annexin A5. The radiochemical purity of 99mTc(I)-his6-annexin A5 after size-exclusion separation was measured by HPLC. The binding affinity of 99mTc(I)-his6-annexin A5 to apoptotic cells was assessed using 20 Gy-irradiated Jurkat T cells. The effectiveness of 99mTc(I)-his6-annexin A5 as an imaging probe to detect the internal tissue apoptosis was assessed by biodistribution study and nanoSPECT/CT using the animal model of C57BL/6J mice conducted with 10 Gy γ irradiation.The radiochemical purity of 99mTc(I)-his6-annexin A5 could attain ≥95%. The binding affinity of 99mTc(I)-his6-annexin A5 to the 20 Gy-irradiated Jurkat cells was found to be ca. 20-fold higher than that to the sham-irradiated cells. In the animal imaging study, the splenic uptake of 99mTc(I)-his6-annexin A5 for the 10 Gy-irradiated mice showed from ca. 3-fold to 5-fold higher than those of the sham-irradiated mice from 45 to 165 min postinjection. The corresponding intestinal uptake showed from ca. 2-fold to 3-fold higher during the same period of time postinjection. The biodistribution study demonstrated the organ uptakes comparable with the imaging results. The apoptotic extents of the spleen and the intestine from the SPECT/CT imaging were correlated with an immunohistochemical staining assay for caspase 3 active form fragment.This work is the first study to demonstrate that 99mTc(I)-his6-annexin A5 is a potential clinical imaging agent for detecting radiation-induced tissue apoptosis in an animal model.
Keywords: Molecular imaging; SPECT/CT; 99mTc(I)-his6-annexin A5; Apoptosis

Comparison of animal studies between interstitial magnetic resonance lymphography and radiocolloid SPECT/CT lymphoscintigraphy in the head and neck region by Naoto Kitamura; Shigeru Kosuda; Koji Araki; Masayuki Tomifuji; Daisuke Mizokami; Akihiro Shiotani; Hiroshi Shinmoto; Hirofumi Fujii; Kiyoshi Ichihara (281-285).
To comparatively assess two techniques, radiocolloid SPECT/CT lymphoscintigraphy and interstitial MR lymphography using SPIO and gadoxetate disodium, in animal models.We used twenty one 8-week-old male nude mice of strain BALB/c Slc-nu/nu, weighing 23–27 g. The 4.7-T MRI equipment was used to detect the SNs. T2*WI of gradient-echo sequences was acquired sequentially up to 24 h after administering SPIO, ferucarbotran. T1WI was acquired sequentially up to 80 min after administering gadoxetate disodium. 99mTc-phytate SPECT/CT lymphoscintigraphy was taken at 30 min after the injection to detect the SNs using animal-dedicated whole-body SPECT/CT hybrid scanner. The injection was submucosally performed in the right tongue margin of each mouse. Reading performances concerning SN visualization and its quality on interstitial MR lymphogram and SPECT/CT lymphoscintigram were performed by 3 radiologists.The SN intensities were 0.43 for the right, 0.61 for the left at 30 min after ferucarbotran injection, with gradual decrease in intensity, and 1.43 for the right, 1.33 for the left at 10 min after gadoxetate disodium injection with a fast decrease in intensity. The base value of 1.0 was at pre-examination. The mean numbers of lymph nodes visualized were 4.00 nodes for on SPECT/CT lymphoscintigram and 2.0 for interstitial MR lymphogram. There was a statistically significant difference in the mean scores between SPECT/CT lymphoscintigraphy and interstitial MR lymphography (two factor mixed design with repeated measures on one factor: p < 0.0002).In our comparative study using mice, the results of radiocolloid SPECT/CT lymphoscintigraphy were superior to those of interstitial MR lymphography, while both SPIO and gadoxetate disodium have a potential of being employed for sentinel node navigation surgery by interstitial MR lymphography in the head and neck region.
Keywords: Sentinel node; 99mTc-phytate; Lymphoscintigraphy; SPECT/CT; Interstitial MR lymphography

RETRACTED ARTICLE: Relationship between 18F-FDG uptake on PET and various biologic molecular markers in benign pulmonary lesion: comparison with primary lung cancer by Kyoichi Kaira; Yasuhisa Ohde; Takehiro Okumura; Kazuo Nakagawa; Toshiaki Takahashi; Haruyasu Murakami; Tateaki Naito; Asuka Tsuya; Yukiko Nakamura; Noboru Oriuchi; Masahiro Endo; Haruhiko Kondo; Takashi Nakajima; Nobuyuki Yamamoto (288-288).