Annals of Nuclear Medicine (v.23, #10)

Bibliometric study of radiation application on microdose useful for new drug development by Fumio Komoda; Akiko Suzuki; Kazuaki Yanagisawa; Tomio Inoue (829-841).
In spite of the sharp increase in both private and government R&D fund, the number of newly approved medicines for market had decreased since the 1990s. This is attributed to a large extent to the bottleneck in the critical path arising from the great disparity between animal model in pre-clinical trial and human model in clinical trial. This bottleneck may be expected to be gotten rid of by change in paradigm of drug development based on microdosing, which is enabled by radiation-related imaging technology. However, this is impossible without being accompanied by interdisciplinary joint researches, in which clinical investigators belonging to medical schools or hospitals play the most decisive role. In this article, authors verify based on bibliometrics that Japan has not employed the opportunity for revitalizing drug research activities because Japanese researchers’ attitude toward radiation technology may not be so positive in comparison with the US, and because the role which clinical investigators play in the phase of pre-clinical trial is smaller in Japan than in the US.
Keywords: Drug development; Critical path; Microdose; Radiation; Bibliometrics

Preparation and evaluation of 186/188Re-labeled antibody (A7) for radioimmunotherapy with rhenium(I) tricarbonyl core as a chelate site by Kazuma Ogawa; Hidekazu Kawashima; Seigo Kinuya; Kazuhiro Shiba; Masahisa Onoguchi; Hiroyuki Kimura; Kazuyuki Hashimoto; Akira Odani; Hideo Saji (843-848).
Rhenium is one of the most valuable elements for internal radiotherapy because 186Re and 188Re have favorable physical characteristics. However, there are problems when proteins such as antibodies are used as carriers of 186/188Re. Labeling methods that use bifunctional chelating agents such as MAG3 require the conjugation of the 186/188Re complex to protein after radiolabeling with the bifunctional chelating agent. These processes are complicated. Therefore, we planned the preparation by a simple method and evaluation of a stable 186/188Re-labeled antibody. For this purpose, we selected 186/188Re(I) tricarbonyl complex as a chelating site. In this study, A7 (an IgG1 murine monoclonal antibody) was used as a model protein. 186/188Re-labeled A7 was prepared by directly reacting a 186/188Re(I) tricarbonyl precursor, [186/188Re(CO)3(H2O)3]+, with A7. We then compared the biodistribution of 186/188Re-labeled A7 in tumor-bearing mice with 125I-labeled A7.For labeling A7, [186/188Re(CO)3(H2O)3]+ was prepared according to a published procedure. 186/188Re-labeled A7 (186/188Re-(CO)3-A7) was prepared by reacting [186/188Re(CO)3(H2O)3]+ with A7 at 43°C for 2 h. Biodistribution experiments were performed by the intravenous administration of 186/188Re-(CO)3-A7 solution into tumor-bearing mice. 186Re-(CO)3-A7 and 188Re-(CO)3-A7 were prepared with radiochemical yields of 23 and 28%, respectively. After purification with a PD-10 column, 186/188Re-(CO)3-A7 showed a radiochemical purity of over 95%. In biodistribution experiments, 13.1 and 13.2% of the injected dose/g of 186Re-(CO)3-A7 and 188Re-(CO)3-A7, respectively, accumulated in the tumor at 24-h postinjection, and the tumor-to-blood ratios were over 2.0 at the same time point. Meanwhile, uptake of 125I-A7 in the tumor was almost the same as that of 186/188Re-(CO)3-A7 at 24-h postinjection. Blood clearances of 186/188Re-(CO)3-A7 were faster than those of 125I-A7. 186/188Re-labeled A7 showed high uptakes in the tumor. However, further modification of the labeling method would be necessary to improve radiochemical yields and their biodistribution.
Keywords: Rhenium; Radioimmunotherapy; Antibody; Tricarbonyl

Prognostic value of myocardial perfusion SPECT images in combination with the maximal heart rate at exercise testing in Japanese patients with suspected ischemic heart disease: a sub-analysis of J-ACCESS by Kenji Ueshima; Akira Yamashina; Satoru Usami; Shinji Yasuno; Osamu Nishiyama; Takuya Yamazaki; Kazuwa Nakao; Tsunehiko Nishimura (849-854).
We assessed whether a combination of summed stress scores (SSS) using exercise myocardial perfusion SPECT (Ex-SPECT) and maximal heart rate accurately predicts cardiac events through a sub-analysis of J-ACCESS (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT) which was conducted to evaluate the prognosis of Japanese patients with suspected ischemic heart disease.In J-ACCESS, 2,373 patients with suspected coronary artery disease not receiving beta-blocker treatment underwent Ex-SPECT. These patients were categorized into the following four groups: Group A [achieved target heart rate (THR) and SSS < 4: n = 631], B (did not achieve THR and SSS < 4: n = 612), C (achieved THR and SSS ≥ 4: n = 570), and D (did not achieve THR and SSS ≥ 4: n = 560). We evaluated the incidence rate of cardiac events including cardiac death, myocardial infarction, and heart failure requiring hospital admission during a 3-year period.In Group A, B, C, and D, 9 of 631 (1.4%), 15 of 612 (2.4%), 23 of 570 (4.0%) and 30 of 560 (5.4%) patients experienced cardiac events, respectively. Although the hazard ratio of the SSS ≥ 4 was 2.45 (p < 0.001) and that of the attained THR was 0.69 (p = 0.10) in the multiple Cox regression analysis, Kaplan–Meier curves showed that the cardiac events rate was lower in the order of A, B, C, and D (p < 0.001).The combination of SSS using Ex-SPECT and the maximal heart rate is a useful predictor of cardiac events in patients with suspected coronary artery disease.
Keywords: Cardiac events; Exercise test; SPECT; J-ACCESS

The purpose of this retrospective study was to evaluate the diagnostic performance of positron emission tomography/computed tomography (PET/CT) with fluorine-18–labeled 2-fluoro-2-deoxy-d-glucose (FDG) in comparison with that of ultrasonography and contrast-enhanced computed tomography (CT) in detecting axillary lymph node metastasis in patients with breast cancer.Fifty patients with invasive breast cancer were recruited. They had received no neoadjuvant chemotherapy and underwent PET/CT, ultrasonography and contrast-enhanced CT before mastectomy. The clinical stage was I in 34 patients, II in 15 patients, and III in one patient. The images of these modalities were interpreted in usual practice before surgery and the diagnostic reports were reviewed for analysis. Sensitivity, specificity, positive predictive value, and negative predictive value of each modality were obtained taking histopathological results of axillary lymph node dissection or sentinel lymph node biopsy as the reference standard.Axillary lymph node metastasis was confirmed in 15 of 50 patients by histopathological studies. PET/CT identified lymph node metastasis in three of these 15 patients. The overall sensitivity and specificity, positive predictive value, and negative predictive value of PET/CT in the diagnosis of axillary lymph node metastasis were 20, 97, 75, and 74%, and those of ultrasonography were 33, 94, 71, and 77% and those of contrast-enhanced CT were 27, 97, 80, and 76%, respectively.PET/CT showed poor sensitivity and high specificity in the detection of axillary lymph node metastasis of breast cancer. Diagnostic performance of PET/CT was not superior to that of ultrasonography and contrast-enhanced CT.
Keywords: Breast cancer; Lymph node metastasis; PET/CT; Ultrasonography; CT

The purpose of this study was to clarify the relationship between reverse redistribution (RRD) of 99mTc-tetrofosmin (99mTc-TF) and left ventricular functional recovery in patients with acute myocardial infarction (AMI).We studied 21 patients with AMI who underwent direct percutaneous coronary intervention (PCI). 99mTc-TF-gated single-photon emission computed tomography (SPECT) was performed at rest in the sub-acute and chronic phases. Imaging data were acquired at 30 min (early images) and 3 h (delayed images) after injection. Defect score, regional relative uptakes of 99mTc-TF (%uptake), and regional wall thickening (WT) were calculated using the 20-segment model. We measured left ventricular ejection fraction (LVEF) and defined ΔLVEF as change in LVEF. Summed defect score was calculated by adding the scores of 20 segments on early and delayed images. Summed washout score (SWS) was derived as the difference between early and delayed scores. We defined that SWS was more than 1 point as individual RRD (I-RRD). In each segment, regional RRD (R-RRD) in the sub-acute phase was calculated as %uptake on early images minus %uptake on delayed images in the sub-acute phase. ΔWT was defined as change in WT from the sub-acute phase to chronic phase. We defined that R-RRD and ΔWT were higher than 1SD on the control map as R-RRD (+) and change of WT (+).All patients were divided into two groups according to the presence of I-RRD. ΔLVEF was significantly higher in I-RRD (+) than in I-RRD (−) (14.5 ± 12.1 vs. 0.0 ± 3.9%, p < 0.01). We analyzed 162 segments as at-risk areas among a total of 420 segments. In total of R-RRD (+), 75 of 96 segments (78%) had change of WT (+), while this was observed in only 13 of 66 segments (20%) in total of R-RRD (−) (p < 0.0001). In addition, there was a significant correlation between R-RRD in the sub-acute phase and change in %uptake on delayed images from the sub-acute phase to chronic phase in at-risk areas (r = 0.584, p < 0.001).These findings suggested that quantitative evaluation of RRD by gated 99mTc-tetrofosmin SPECT in the sub-acute phase can predict recovery of left ventricular function in the chronic phase with higher accuracy in patients with AMI who underwent direct PCI.
Keywords: Acute myocardial infarction; Reverse redistribution of 99mTc-tetrofosmin; Left ventricular functional recovery

Impact of additional SPECT in bone scanning in tumor patients with suspected metastatic bone disease by Ivayla Apostolova; Elif Gölcük; Karl Heinz Bohuslavizki; Ralph Buchert; Winfried Brenner (869-875).
The aim of this study was to investigate the additional value of single-photon emission computed tomography (SPECT) for patient staging compared to planar bone scanning in an unselected cohort of cancer patients.The study included 271 consecutive tumor patients in whom planar imaging and two-bed position SPECT of the spine and the pelvis had been performed. Retrospective image interpretation was performed independently for planar and SPECT scans. Findings were categorized as ‘benign’, ‘equivocal’, or ‘malignant’ on a lesion base, and as ‘no metastatic disease’, ‘equivocal’, or ‘metastatic disease’ on a patient base.447 lesions were detected by SPECT. Missing of lesions in planar images was rare (4.3% of all SPECT lesions). Planar findings differed from SPECT findings in 149 lesions (33.3%). Most of these ‘inconsistent’ lesions were rated as equivocal in the planar images but benign (14.5% of all lesions) or malignant (11.0%) by SPECT. On a patient base, 81.6% of patients with planar equivocal staging were classified as either benign (55.3%) or malignant (26.3%) by SPECT. Patients definitively staged as ‘no metastatic disease’ or ‘metastatic disease’ in planar images were staged differently by SPECT in only 3.7% of cases (up-staging in 2.6% and down-staging in 1.1%).Single-photon emission computed tomography changed a definite staging as based on planar images in less than 4% of the patients. In patients with planar equivocal staging, however, SPECT allowed a definite diagnosis in more than 80% of these cases, and, thus, should be performed routinely in patients with equivocal findings.
Keywords: Bone scintigraphy; Tc-99m methylene diphosphonate; SPECT; Metastatic bone disease

Donepezil- and scopolamine-induced rCMRglu changes assessed by PET in conscious rhesus monkeys by Makoto Asai; Akihiko Fujikawa; Akihiro Noda; Sosuke Miyoshi; Nobuya Matsuoka; Shintaro Nishimura (877-882).
[18F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is a useful tool for measuring the regional cerebral metabolic rate of glucose (rCMRglu), which is an index of neuronal activity. Donepezil, an acetylcholine esterase inhibitor (AChEI), has been recommended as a treatment option for patients with Alzheimer’s disease (AD). We aimed to characterize the effects of donepezil on rCMRglu using FDG-PET in non-human primates.We investigated the effects of administration of donepezil (500 μg/kg, i.m.), the non-selective muscarinic ACh receptor antagonist scopolamine (30 μg/kg, i.m.), and the coadministration of both drugs on the rCMRglu of conscious young rhesus monkeys.Donepezil increased the rCMRglu in all regions of interest except in the thalamus. Scopolamine treatment also increased the rCMRglu in all regions of interest except the cerebellum and thalamus. However, these effects disappeared with coadministration of the drugs.This PET study showed that administration of donepezil or scopolamine alone increased the rCMRglu in conscious rhesus monkeys. We also found that the donepezil-induced increase was abolished by simultaneous administration of scopolamine, suggesting that muscarinic ACh receptor function plays an important role in the effect of donepezil.
Keywords: FDG-PET; Donepezil; Scopolamine; Muscarinic ACh receptor; Rhesus monkey

FDG PET findings in a case with acute pulmonary silicosis by Metin Özkan; Aslı Ayan; Deniz Arik; Arzu Balkan; Önder Öngürü; Seyfettin Gümüş (883-886).
A 21-year-old male having a history of 4 years of working at a denim factory as a sandblaster was diagnosed with pulmonary silicosis and he was also an active smoker. Productive cough, dyspnea on effort, night sweats, and weight loss in a short period of time were his complaints. Chronic occupational exposure to tiny particles of silicon dioxide can stimulate parenchymal inflammation, collagen synthesis and, ultimately pulmonary fibrosis called silicosis. A typical history of exposure and chest X-ray is usually enough for diagnosis. No effective treatment exists except supportive care. Although chest X-ray of the patient revealed bilateral disseminated micronodular densities, a peripherally diffuse prominent FDG [(F-18)-2-fluoro-2-deoxy-D-glucose] uptake in both lungs and faint FDG uptake in mediastinal lymph nodes demonstrating active inflammation regions were noted on PET (Positron Emission Tomography) scan. This case was presented to show the active disease discriminated by FDG PET from chronic changes detected by radiological studies. FDG PET can provide additional information to CT regarding the diagnosis of acute silicosis and the rare accelerated silicosis.
Keywords: Silicosis; Occupational diseases; Positron emission tomography; PET

Intense accumulation of 18F-FDG, not enhancement on MRI, helps to guide the surgical biopsy accurately in soft tissue tumors by Jong Hoon Park; Eun Kyung Park; Chang Ho Kang; Chul Hwan Kim; Jae Gol Choe; Won Noh (887-889).
Soft tissue sarcomas are a highly heterogeneous group of malignancies that arise from mesenchymal tissues. Grading of soft tissue sarcomas is an important prerequisite for the choice of therapy and estimation of prognosis. However, incisional biopsy of huge soft tissue sarcoma lesions frequently fails to provide an accurate diagnosis when there is a benign component, cystic changes and/or necrosis. MRI is helpful in evaluating the extent of the sarcoma lesion, vascularization, invasiveness and integrity of surrounding tissue, but definitive differentiation of benignity and malignancy is not possible with it. In this study, positron emission tomography using [18F]-2-fluoro-2-deoxy-d-glucose successfully guided surgeons to identify the most hypermetabolic and, therefore, the most suitable biopsy sites of huge soft tissue sarcoma.
Keywords: Soft tissue tumor; Sarcoma; FDG PET; MR; Metabolic biopsy