Annals of Nuclear Medicine (v.22, #10)

Usefulness of triple-phase thallium-201 SPECT in non-small-cell lung cancer (NSCLC): association with proliferative activity by Seigo Fujita; Shigeki Nagamachi; Hideyuki Wakamatsu; Ryuichi Nishii; Shigemi Futami; Shozo Tamura; Yasunori Matsuzaki; Toshio Onizuka; Kinta Hatakeyama; Yujiro Asada (833-839).
The conventional delayed scan in dual phase of thallium-201 (201Tl) single-photon emission computed tomography (SPECT) is useful for estimating the viability of non-small-cell lung cancer (NSCLC). However, the influence of tumor blood flow cannot be ignored by the scan at 4 h after the tracer injection. For the purpose of improving the diagnostic capability and for clarifying the association between 201Tl uptake and proliferative activity, we investigated the usefulness of super-delayed scan obtained at 24 h in triple-phase 201Tl SPECT.A total of 122 patients with lung nodule, 106 of NSCLC and 16 of benign nodule, were given 201Tl SPECT before the tumor resection. Early image (15 min), delayed image (4 h), and super-delayed image (24 h) were obtained after intravenous injection of 201Tl chloride (111 MBq). On the each SPECT image, regions of interest (ROIs) were placed over the tumor contour (T) and contra-lateral normal lung tissue (N) area on one transverse view clearly defined lesions, and T/N ratio on the early image (ER), the delayed image (DR), and the super-delayed image (sDR), and retention indexes (RI and sRI) were calculated. All patients underwent subsequent surgical excision, and the specimens were immunostained for Ki-67 and CD34. The proliferative capability was measured as a percentage of positive nuclear area for Ki-67 (MIB-1 index). The angiogenesis was measured density of positive micro-vessels for CD34 (micro-vessel density, MVD). Correlation analysis was performed to evaluate the relationship between the MIB-1 index, MVD, and SPECT parameters.The diagnostic accuracy of sDR in the differential of NSCLC was higher than that of DR (83.6% vs. 91.8%). Both DR and sDR were positively correlated with MIB-1 index. The correlation coefficient was higher in sDR (0.53 vs. 0.69). The MIB-1 index of the increasing pattern (RI < sRI) group was significantly higher (P < 0.001) than that of the decreasing pattern (RI > sRI) group.The super-delayed scan in the triple-phase 201Tl SPECT is more useful than conventional delayed scan for both the diagnostic capability and assessing proliferation of NSCLC.
Keywords: Triple-phase 201Tl SPECT; Super-delayed image; Proliferation; NSCLC

Adenosine A1 receptors using 8-dicyclopropylmethyl-1-[11C]methyl-3-propylxanthine PET in Alzheimer’s disease by Nobuyoshi Fukumitsu; Kenji Ishii; Yuichi Kimura; Keiichi Oda; Masaya Hashimoto; Masahiko Suzuki; Kiichi Ishiwata (841-847).
Adenosine is an endogenous modulator of synaptic functions in the central nervous system. The effects of adenosine are mediated by at least four adenosine receptor subtypes. Decreased density of adenosine A1 receptors, which is a major subtype adenosine receptor in the hippocampus, has been reported in vitro in Alzheimer’s disease. We evaluated adenosine A1 receptor in the brain of elderly normal subjects and patients with Alzheimer’s disease (n = 8 and 6, respectively), using positron emission tomography (PET) and 8- dicyclopropylmethyl-1-[11C]methyl-3-propylxanthine ([11C]MPDX).A 60-min PET scan with [11C]MPDX was performed. The patients with Alzheimer’s disease also underwent PET with [18F]fluorodeoxyglucose (FDG). The binding potential of [11C]MPDX was quantitatively calculated in the regions of interest (ROIs) placed on the frontal, medial frontal, temporal, medial temporal, parietal, and occipital cortices, striatum, thalamus, cerebellum, and pons. Statistical parametric mapping (SPM2) was used for analysis of [11C]MPDX and FDG-PET.In the ROI-based analysis, the binding potential of [11C]MPDX in patients with Alzheimer’s disease was significantly lower in the temporal and medial temporal cortices and thalamus than that in elderly normal subjects (P = 0.038, 0.028, and 0.039, respectively). SPM analysis also showed significant decreased binding potential in the temporal and medial temporal cortices and thalamus in patients with Alzheimer’s disease. FDG uptake was significantly decreased in the temporoparietal cortex and posterior cingulate gyrus.Decreased binding of [11C]MPDX in patients with Alzheimer’s disease was detected in temporal and medial temporal cortices and thalamus. This pattern possibly differed from the hypometabolism pattern of FDG. [11C]MPDX PET is valuable for the detection of degeneration in the temporal and medial temporal cortices and corticothalamic transmission, and may provide a different diagnostic tool from FDG-PET in brain disorders such as Alzheimer’s disease.
Keywords: [11C]MPDX; Adenosine A1 receptor; Medial temporal cortex; Positron emission tomography; Alzheimer’s disease

Efficacy and safety of 32P-nanocolloid for treatment of distant lymph node metastasis in VX2 tumor-bearing rabbits by Shengxiang Dong; Gang Huang; Penan Liu; Yubo Ma; Weili Yan; Liangrong Wan; Changqing Zhu (849-858).
Eradication of micrometastases present in lymph nodes of cancer patients improves their prognosis significantly. Radionuclide therapy possesses the potential to eliminate such metastases.This study was performed to evaluate the efficacy and safety of 32P-nanocolloid therapy in the treatment of distant carcinoma cell metastases in lymph nodes of VX2 tumor-bearing rabbits.To obtain VX2 tumor micrometastases in right armpit lymph nodes of 12 male New Zealand white rabbits, VX2 tumors were implanted by hypodermal inoculation into the right anterior limb. Animals were randomly divided into therapy (n = 6) and control (n = 6) groups. 32P-nanocolloid (0.5 mCi), 95% of which was >50 nm in diameter, was administered to the therapy group, and saline was administered to the control group. Injections were given once weekly for 4 weeks.2-Deoxy-2[18F]-fluoro-d-glucose positron emission tomography revealed that the number of involved lymph nodes and the maximum standardized uptake value decreased in the 32P-nanocolloid therapy group as compared with the baseline or saline control grou0 (P < 0.05). The expression of the lymphangiogenesis factors vascular endothelial growth factors (VEGF)-C and VEGF-D by VX2 tumor cells present in lymph nodes was significantly lower in the therapy group as compared with the control group. Additionally, apoptotic VX2 tumor cell death was significantly greater in lymph nodes of the therapy as compared with the control group (P < 0.01). With the exception of a decrease in white blood cells of peripheral blood (P < 0.05), standard laboratory values were unaffected throughout the course of therapy with 32P-nanocolloid.These findings support treatment with 32P-nanocolloid as a safe and effective approach for eradication of lymph node micrometastases.
Keywords: 32P-nanocolloid; Distant lymph node metastases; VX2 carcinoma cells; VEGF-C; VEGF-D

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111 by Frantisek Trejtnar; Zbynek Novy; Milos Petrik; Alice Laznickova; Ludmila Melicharova; Marie Vankova; Milan Laznicek (859-867).
Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA0, Tyr3, Thr8]-octreotide (DOTA-TATE) and [DOTA0, 1-Nal3]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods.The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells.The renal clearance of 111In-DOTA-NOC in the perfused rat kidney was significantly lower than that of 111In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. 111In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than 111In-DOTA-TATE (ratio 3: 1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin > maleate > lysine. The uptake of the radiopeptides in the renal cells was temperature dependent.Both in vitro methods showed a higher renal accumulation of 111In-DOTA-NOC in comparison with 111In-DOTA-TATE. The renal uptake was partly decreased by inhibitors of receptor-mediated endocytosis and by a block of energy-dependent processes. A significant participation of active transport processes in renal accumulation of the studied peptides was confirmed.
Keywords: Somatostatin analog; Renal elimination; Antitumor agents; Radiodiagnostics; Radiotheraphy

Validation of fast-RAMLA in clinical PET by Hidetaka Sato; Keiichi Cho; Yoshimitsu Fukushima; Masato Shiiba; Kenta Hakozaki; Tomonari Kiriyama; Minoru Sakurai; Kouji Kanaya; Shin-ichiro Kumita (869-876).
Images using the fast row action maximum likelihood algorithm (fast-RAMLA), which employs half-interpolated sinograms of conventional 3DRAMLA, are immediately generated following positron emission tomography (PET) scanning and are invariably produced in the process of line-of-response RAMLA (LOR-RAMLA) reconstruction. We quantitatively and visually compared the clinical validity of dual time point [18F]-FDG imaging with fast-RAMLA and LOR-RAMLA.An International Electrotechnical Commission (IEC) phantom was established in which the ratio of the activities in the hot sphere was set up and a background of 3.8:1 was scanned and reconstructed using both algorithms. The contrast recovery coefficient was then calculated. The clinical study retrospectively analyzed 35 patients (25 men and 10 women; age range 30–84 years; mean age 63.9 years) with confirmed specific pathological lesions or clinical follow-up; 21 of the patients had 51 malignant lesions and 15 had 23 benign lesions. The maximum standard uptake value (SUVmax) was measured in all lesions using LOR-RAMLA. The maximal counts of all lesions determined manually were divided by the average count of bilateral ventricles and the aortic arch for standardization on fast-RAMLA, and the values were compared with the SUVmax of LORRAMLA. Inter-observer variation in detection was determined among three radiologists who blindly reviewed and scored 70 maximum intensity projection images from 35 patients reconstructed using LORRAMLA and fast-RAMLA.We identified a quantitative correlation and determined the visual quality of lesion detection between fast-RAMLA and LOR-RAMLA and indicated usefulness and improvement point on fast-RAMLA.Fast-RAMLA can improve the strategy for using dual time point [18F] fluorodeoxyglucose positron emission tomography ([18F]-FDG-PET) and increase the efficiency of the [18F]-FDG-PET scanner.
Keywords: RAMLA; PET; Dual time point; 18F-FDG

Renal cortical involvement in children with first UTI: does it differ in the presence of primary VUR? by Gül Ege Aktaş; Sabahat Inanır; Halil Turgut Turoğlu (877-881).
The aim of this study was to investigate the influence of vesicoureteral reflux (VUR) on dimercaptosuccinic acid (DMSA) scintigraphic patterns in children with first symptomatic urinary tract infection (UTI).A total of 45 children with the diagnosis of first symptomatic UTI (28 girls, 17 boys, mean age 18 months, range 1 month-11 years) were reviewed. All DMSA scans were obtained within 2 months of bacteriologically proven UTI (median 21 days, mean 26 ± 21, 14). After the exclusion of the patients with bilateral cortical lesions, 82 renal units were analyzed. The scintigraphic patterns included regional and global description of renal cortical abnormality (normal or decreased differential renal function, regional renal function (RRF), and the number and severity of cortical lesions).Vesicoureteral reflux was detected in 26 (32%) renal units (15 with grade 1–2, 11 with grade 3–4). Renal cortical abnormality was observed in 10 renal units without VUR (10/56, 17%) and 13 renal units with VUR (13/26: 50%). Of the 15 renal units, 5 with grade 1–2 VUR (5/15) and 8 of the 11 renal units with grade 3–4 VUR (8/11) had renal cortical involvement. The most common scintigraphic pattern in the patients without VUR was the preserved RRF (≥45%) and two or fewer photon-deficient areas. On the other hand, a decreased RRF (<45) associated with cortical lesions was the most frequent finding in patients with refluxing kidneys (8/26, 30%), especially in those with grade 3–4 disease.This investigation showed that the presence of VUR affects DMSA patterns in children with first symptomatic UTI.
Keywords: VCUG; DMSA; Reflux; Pyelonephritis

Accelerator mass spectrometry analysis of background 14C-concentrations in human blood: aiming at reference data for further microdosing studies by Ryogo Minamimoto; Yoshimi Hamabe; Teiji Miyaoka; Takamitsu Hara; Keisuke Yoshida; Takashi Oka; Tomio Inoue (883-889).
Phase 0 clinical studies, which are known as microdose trials, are expected to promote drug development and reduce development costs. The accelerator mass spectrometry (AMS) system is expected to play an important role in the microdosing tests, as it is a highly sensitive measurement system that can be used to determine the drug concentrations in these tests. Using the AMS system, we measured the background 14C-concentration in human blood and evaluated the data for use as a reference in microdose studies that administer 14C-labeled compounds in humans.Blood samples of five healthy Japanese volunteers (three men, two women, median age 40.4 ± 9.8 years) were collected around the same time and just prior to when the subjects ate a meal (between 12:00 noon and 2:00 pm). Centrifugal separations of blood that was allowed to clot and the plasma were performed at 503 g for 2 min at 4°C. Background 14C-concentration for each of the samples was measured using the AMS system. The Institute of Accelerator Analysis, which is the first contract research organization in Japan that is capable of providing AMS analysis services for carbon dating and bioanalysis work, performed the AMS analysis.The mean 14C-concentration in blood was 1.613 ± 0.125 dpm/ml (men 1.668 ± 0.114 dpm/ml, women 1.514 ± 0.076 dpm/ml), in clots 2.373 ± 0.087 dpm/ml (men 2.381 ± 0.101 dpm/ml, women 2.357 ± 0.060 dpm/ ml), and in plasma 0.648 ± 0.049 dpm/ml (men 0.647 ± 0.059 dpm/ml, women 0.649 ± 0.032 dpm/ml). The coefficient variation (CV) for blood was 7.8% (men 6.9%, women 5.0%), for clots 3.7% (men 4.3%, women 2.5%), and for plasma 7.6% (men 9.1%, women 4.9%). The 14C-concentrations of the clot and blood were higher than those of plasma. The 14C-concentrations in the blood and plasma were slightly different between individuals when compared with the values for the clot, although the differences were quite small, with a CV value less than 7.8%.Even though the 14C-concentration differed only slightly between individuals, 14C-concentrations of the clot and blood were higher than those of the plasma. Therefore, the variation and difference of the background data for blood and plasma might be of use as a reference for microdosing test evaluations.
Keywords: Accelerator mass spectrometry; Background; 14C; Phase 0 clinical study; Microdose

The event risk of patients with coronary heart disease may be estimated by a large-scale prognostic database in a Japanese population. The aim of this study was to create a heart risk table for predicting the major cardiac event rate.Using the J-ACCESS database created by a prognostic investigation involving 117 hospitals and >4000 patients in Japan, multivariate logistic regression analysis was performed. The major event rate over a 3-year period that included cardiac death, non-fatal myocardial infarction, and severe heart failure requiring hospitalization was predicted by the logistic regression equation. The algorithm for calculating the event rate was simplified for creating tables.Two tables were created to calculate cardiac risk by age, perfusion score category, and ejection fraction with and without the presence of diabetes. A relative risk table comparing age-matched control subjects was also made. When the simplified tables were compared with the results from the original logistic regression analysis, both risk values and relative risks agreed well (P < 0.0001 for both).The Heart Risk Table was created for patients suspected of having ischemic heart disease and who underwent myocardial perfusion gated single-photon emission computed tomography. The validity of risk assessment using a J-ACCESS database should be validated in a future study.
Keywords: J-ACCESS study; Ischemic heart disease; Cardiac events; Prognosis

Incremental prognostic value of 99mTc-tetrofosmin myocardial SPECT after percutaneous coronary intervention by Panagiotis Georgoulias; Chara Tzavara; Nikolaos Demakopoulos; Stavroula Giannakou; Varvara Valotassiou; Ioannis Tsougos; Petros Xaplanteris; Ioannis Fezoulidis (899-909).
Percutaneous transluminal coronary angioplasty is a well-established therapeutic method in selected patients with coronary artery disease. The aim of this study was to assess the incremental prognostic value of technetium-99m (99mTc)-tetrofosmin myocardial gated-single- photon emission computed tomography (SPECT) in asymptomatic patients after coronary artery stenting.A total of 246 consecutive patients (aged 55.5 ± 8.2 years, 182 men) participated in the study with a median follow-up of 9.5 years (interquartile ra 5.8–10.5 years). All patients underwent exercise gated-SPECT myocardial imaging within 5–7 months. Myocardial scintigrams were performed using 99mTctetrofosmin, and were evaluated calculating the summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) indexes. Cardiovascular death and non-fatal myocardial infarction were considered as hard cardiac events, and late revascularization (>3 months after myocardial SPECT) procedures as soft events. Receiver-operating characteristic (ROC) analysis was used to test the prognostic ability of SSS and SDS for cardiac events. Cox proportional hazards models were used to evaluate the incremental value of SPECT variables.Cardiac death occurred in 12 (4.9%) patients and non-fatal myocardial infarction in 20 (8.1%) patients. In addition, 60 (24.4%) patients underwent a late revascularization procedure. Using ROC analysis the optimal cut-offs of SSS (AUC = 0.94; 95% CI 0.92–0.97) and SDS (AUC = 0. 76; 95% CI 0.70–0.82) for the prediction of cardiac events were 10 and 1.7, respectively. Multiple Cox regression analyses revealed that SSS > 10 (HR = 24.2; 95% CI 7.44–78.79) and SDS > 1.7 (HR = 2.72; 95% CI 1.23–6.00) provided incremental prognostic value over clinical and exercise test data for the composite end points of any cardiac event. 99mTc-tetrofosmin myocardial gated- SPECT, performed 6 months post-percutaneous coronary intervention (PCI), provides incremental prognostic information for the prediction of cardiac events in asymptomatic patients after PCI.
Keywords: Incremental prognostic value; PCI; Myocardial SPECT; 99MTC-tetrofosmin

Value of analyzing deep gray matter and occipital lobe perfusion to differentiate dementia with Lewy bodies from Alzheimer’s disease by Soichiro Shimizu; Haruo Hanyu; Kentaro Hirao; Tomohiko Sato; Toshihiko Iwamoto; Kiyoshi Koizumi (911-916).
Dementia with Lewy bodies (DLB) is generally characterized by a decrease in regional cerebral blood flow (rCBF) in the occipital lobe. However, not all patients with DLB have this feature. We explored characteristics of rCBF pattern changes to improve the identification of DLB, in addition to occipital hypoperfusion.The study population comprised 30 patients with probable DLB and 49 patients with probable Alzheimer’s disease (AD) who underwent single-photon emission computed tomography. The data were analyzed using Neurological Statistical Image Analysis Software (NEUROSTAT). We established a template of the region of interest (ROI) presenting the parietal lobe, posterior cingulate, striatum, thalamus, and occipital lobe on the standard brain atlas. We then compared the mean Z scores in each ROI between DLB and AD. Moreover, we investigated the value of analyzing relative rCBF changes in both the deep gray matter and occipital lobe in differentiating DLB from AD.The DLB group showed a significant relative rCBF increase in the bilateral striatum and thalamus, and a significant relative rCBF decrease in the bilateral occipital lobe when compared with the AD group. Receiver-operating characteristic analysis revealed that determining the hyperperfusion in the thalamus together with the hypoperfusion in the occipital lobe enabled a more accurate differentiation between DLB and AD than studying individual areas.Studying the relative increase of rCBF in the deep gray matter, and the relative decrease of that in the occipital lobe achieved a high differentiation between DLB and AD. This suggests that determining both an increase and a decrease in rCBF pattern may be important in differentiating between the two diseases.
Keywords: SPECT; Dementia with Lewy bodies; Alzheimer’s disease; Cerebral blood flow; Deep gray matter

Radio-iodine therapy and Helicobacter pylori infection by Ali Gholamrezanezhad; Sahar Mirpour; Mohsen Saghari; Javaher Abdollahzadeh; Aydin Pourmoslemi; Sarah Yarmand (917-920).
Helicobacter pylori is the most important cause of gastritis and related morbidities. Following consumption, radioactive iodine accumulates considerably in the stomach. On the basis of this observation, we decided to determine whether the high radiation induced by radio-iodine in the stomach is effective in the eradication of this infection.All consecutive patients with differentiated thyroid carcinoma, who were referred for radio-iodine therapy [dose 117.1 ± 24.4 mCi (4.3 ± 0.9 GBq), range 100–200 mCi (3.7–7.4 GBq)], were enrolled. To detect H. pylori infection, the urease breath test (UBT) was performed 1-2 h before radio-iodine consumption and the test was repeated 2 months later.Of 88 patients, 71 had pre-treatment positive UBT. Of these, 23 patients had negative post-treatment result, which means a significant reduction (26.1%, 95% CI 16.8–35.5%) in the number of positive UBT results in our treated population (32.4% of UBT-positive cases became UBT-negative).Considering the high prevalence of reinfection in developing countries, the therapeutic benefit would have been more considerable if the second UBT had been done with a lag time of less than 2 months. Although radio-iodine therapy is not a logical method for the treatment of patients suffering from H. pylori, our finding provides indirect evidence about the radiosensitivity of bacteria, the future clinical applications of which need to be further evaluated. Also this finding can be useful for the food industry, where radiation is used widely to sterilize food. Regarding the possibility of H. pylori suppression, we recommend not using UBT for screening for the infection for at least within 2 months following radio-iodine therapy.
Keywords: Radioactive iodine; Helicobacter pylori ; Urease breath test

Comparison of SPM and NEUROSTAT in voxelwise statistical analysis of brain SPECT and MRI at the early stage of Alzheimer’s disease by Masaki Nishimiya; Hiroshi Matsuda; Etsuko Imabayashi; Ichiei Kuji; Noriko Sato (921-927).
Neuroimaging plays a major role in the early diagnosis of Alzheimer’s disease (AD). Recent advances in voxelwise statistical analysis after anatomic standardization of images have made this early diagnosis easier and more objective than visual inspection. We present comparative observations of NEUROSTAT, statistical parametric mapping (SPM) 99, and SPM2 in the early diagnosis of AD using brain perfusion single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI).We performed voxel-by-voxel statistical group analysis for brain perfusion SPECT and gray matter images segmented from MRI between 61 patients with very early AD and 82 age-matched healthy volunteers. Anatomic standardization was performed using NEUROSTAT, SPM99, and SPM2 using both original and common templates.The location of significant reduction of regional cerebral blood flow (rCBF) for SPECT and gray matter concentration for MRI were identical among these three methods irrespective of the templates used. When using the original template, the significance of peak rCBF reduction in the posterior cingulate gyri was higher in SPM99 and SPM2 than that in NEUROSTAT. On the other hand, when using the common template, the significance of peak rCBF reduction in the posterior cingulate gyri was higher in NEUROSTAT and SPM2 than that in SPM99. NEUROSTAT showed almost the equal significance of peak rCBF reduction between the used templates. Almost the equal significance of reduction in gray matter concentration was observed in the parahippocampal gyri among the three methods.NEUROSTAT, SPM99, and SPM2 showed identical location of significant reductions in rCBF and gray matter concentration in very early AD patients. Used templates for anatomic standardization are relevant to the results of voxelwise statistical analysis in SPM, less prominently in SPM2 than in SPM99, whereas irrelevant in NEUROSTAT.
Keywords: SPM; NEUROSTAT; Alzheimer’s disease; SPECT; MRI