4′-[methyl- 11 C]-thiothymidine as a proliferation imaging tracer for detection of colorectal cancer: comparison with 18 F-FDG Abstract Objective The novel radiotracer, 4′-[methyl-11C]-thiothymidine (11C-4DST), was developed based on the DNA incorporation method as a cell proliferation marker. This study investigated the feasibility of 11C-4DST positron emission tomography/computed tomography (PET/CT) for detection of colorectal cancer, as compared with 2-deoxy-2-18F-fluoro-d-glucose (18F-FDG) PET/CT, and to correlate the two radiotracers with proliferative activity. Methods A total of 18 patients with newly diagnosed colorectal cancer underwent both 11C-4DST and 18F-FDG PET/CT. Tumor lesions were identified as areas of focally increased uptake, exceeding that of adjacent normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUVmax) was calculated. Proliferative activity as quantified by the Ki-67 index was estimated in tumor specimens. Results In all 18 patients, colorectal cancers were detected by both 11C-4DST and 18F-FDG PET/CT. The median (± SD) SUVmax for 11C-4DST (6.02 ± 2.55) was significantly lower than that for 18F-FDG (13.91 ± 7.62) (P < 0.001). 11C-4DST SUVmax and 18F-FDG SUVmax showed a significant correlation (r = 0.69, P = 0.002). 11C-4DST SUVmax and Ki-67 index were weakly correlated (r = 0.50, P = 0.04). 18F-FDG SUVmax and Ki-67 index were not significantly correlated (r = 0.44, P = 0.06). Conclusions Despite a significantly lower uptake of 11C-4DST than that of 18F-FDG, detection of colorectal cancer was also feasible with 11C-4DST PET/CT. 11C-4DST PET/CT might have a role in the noninvasive assessment of proliferation in colorectal cancer.

Searching for diagnostic properties of novel fluorine-18-labeled d -allose Abstract Objective Two fluorine-18-labeled analogues, 3-deoxy-3-[18F]fluoro-d-allose (3-[18F]FDA) and 6-deoxy-6-[18F]fluoro-d-allose (6-[18F]FDA), were synthesized and their potentials of diagnostic property were characterized. Methods In vitro rat red blood cell (RBC) transport and phosphorylation by yeast hexokinase were evaluated in comparison with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). The rate of protein binding in pooled human serum was measured by an ultrafiltration method. In vivo metabolite analysis in mice was also performed. Biodistribution, urine excretion, and in vivo renal kinetics in mice were compared with 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS). Results Rat RBC uptake of 3- and 6-[18F]FDA (7.8 ± 2.5%ID and 10.2 ± 4.8%ID, respectively) was significantly lower than that of [18F]FDG (44.7 ± 8.7%ID). RBC uptake of 3-[18F]FDA was inhibited by d-glucose (30%) and cytochalasin B (40%), indicating the involvement of GLUT1-dependent transport. In contrast, 6-[18F]FDA transport was not inhibited by d-glucose and cytochalasin B. 3- and 6-[18F]FDA were not phosphorylated by yeast hexokinase under the conditions that result in 60% conversion of [18F]FDG into [18F]FDG-6-phosphate within 30 min. Serum protein binding of 3- and 6-[18F]FDA was negligible. Metabolic transformation of both tracers was not detected in plasma and urine at 30 min after injection. The highest tissue uptake of both tracers was observed in kidneys. Heart and brain uptake of both tracers was below blood levels throughout the biodistribution studies (until 120 min after injection). No significant uptake in the bone was observed, indicating the absence of de-fluorination in mice. In vivo PET imaging visualized rapid excretion of the administered 3- and 6-[18F]FDA from the kidneys, with minimal tracer accumulation in other organs. The urine excretion rate of 3-[18F]FDA was much lower than that of 6-[18F]FDA and [18F]FDS. Conclusions 3- and 6-[18F]FDA might be unsatisfactory for tumor imaging. In contrast, these tracers demonstrated high levels of kidney uptake and excretion, low serum protein binding, and high metabolic stability as preferable properties for renal imaging. Notably, the urine excretion rate and kidney uptake kinetics of 6-[18F]FDA were comparable with those of the potential renal imaging agent [18F]FDS. Further validation studies in animal models are required to confirm the feasibility of 6-[18F]FDA as a functional renal imaging agent.

In vivo preclinical PET/CT imaging of carbon-11-labeled aminoglycerol probe for the diagnosis of liver fibrosis Abstract Objective As an important membrane protein, aquaglyceroporin involves liver glycerol metabolism, which can be used to stage liver fibrosis. In this study, we synthesized a novel molecular probe carbon-11-labeled AR ([11C]AR) with aminoglycerol (AR), and evaluated its preclinical performance for liver fibrosis diagnosis by positron emission tomography/computed tomography (PET/CT) imaging in vivo. Methods We developed a fully automatic synthesis procedure for the preparation of [11C]AR by radiolabeling glycerol analogue precursor AR with carbon-11. The liver uptake kinetics of [11C]AR was investigated using a rat model by the PET/CT scanner. The dynamic PET/CT scans were performed between the control group (n = 5) and experimental group (n = 25), which was divided into three subgroups (S1, S2 + S3, S4) based on the stages of liver fibrosis. The regions of interest (ROIs) of 20 pixels were drawn in the liver area on the reconstructed images. One-way analysis of variance and independent sample t test were used to analyze the statistical difference of the maximum standardized uptake value (SUVmax) among the groups at series of scanning time points (20 s, 60 s, 90 s, 150 s, 5 min, 10 min, 20 min and 25 min). Results The fully automatic synthesis of [11C]AR was successfully achieved with high synthesis efficiency (above 50%). The uptake of [11C]AR in progressive liver fibrosis tissues was significantly lower than that in healthy livers at all the imaging time points (P < 0.05), especially at early time points (before 10 min p.i.). A cut-off SUVmax value (1.1) at 150 s p.i. was set for discrimination progressive fibrosis from healthy liver. More experimental and healthy rats were tested with this new threshold to evaluate fibrosis situation. The sensitivity of detecting progressive fibrosis with [11C]AR was 100% in the second cohort. Conclusion We demonstrated a new carbon-11-radiolabeled aminoglycerol PET/CT imaging probe [11C]AR for liver fibrosis diagnosis and staging, which may allow potential assessment of liver fibrosis stages in a rapid and noninvasive method.

Impact of decompressive craniectomy on brain perfusion scintigraphy as an ancillary test for brain death diagnosis Abstract Objectives Decompressive craniectomy is occasionally performed for patients with impending brain death, which is intended to relieve critically elevated intracranial pressure to keep effective intracranial perfusion. It has been in debate if this surgery later affects the result of brain perfusion scintigraphy performed as an ancillary test in the course of brain death diagnosis because rigid closed skull is deemed essential to elevate intracranial pressure to the point of total absence of intracranial radiotracer uptake on scintigraphy. The purpose of this study is to elucidate the impact of decompressive craniectomy on the result of brain perfusion scintigraphy in patients with suspected brain death. Methods This retrospective cross-sectional study included consecutive 151 brain perfusion scintigraphy performed in 138 patients with suspected brain death from various causes (male 82 patients, female 56 patients; range 0–74 years; mean age 36.6 years). All exams were indicated due to inconclusive clinical diagnosis of brain death. The scintigraphy protocol consists of immediate flow phase and delayed parenchymal phase planar imaging. Additional SPECT imaging was performed in 15 studies in 14 patients. The results, positive or negative brain flow, were compared between patients with and without decompressive craniectomy using Chi-squared test. As there were patients with repeat studies, analysis was performed for both initial and final exam results. Same dataset was used for initial and final exams in patients with only one exam. Results Out of 138 patients, 15 patients underwent decompressive craniectomy (11%) and 123 patients were managed medically (89%). On the initial exam, negative brain flow was demonstrated in 11 of 15 patients with craniectomy (73.3%) and 106 of 123 patients without craniectomy (86.2%). On the final exam, negative brain flow was demonstrated 12 of 15 patients with craniectomy (80%) and 111 of 123 patients without craniectomy (90.2%). There were no statistically significant differences between the two groups on both initial and final exams (p = 0.19 and 0.23, respectively). Conclusion In patients with suspected brain death, history of decompressive craniectomy does not affect the result of brain perfusion scintigraphy.

Effect of drugs containing glucose on FDG-PET image quality Abstract Objective Patients often take prescription drugs for various diseases or complications that contain several grams of glucose. However, the effect of these glucose-containing medications on the image quality of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has not been established. This study aimed to evaluate the effect of taking drugs containing glucose before an FDG-PET on the PET image quality. Methods In total, 736 continuously enrolled patients who underwent FDG-PET were retrospectively analysed. We investigated the total glucose content in the prescription drugs that each patient took during fasting before the FDG injection, and we divided the patients into three groups according to the amount of glucose in their drugs: group A did not take any drugs containing glucose, group B took sugar-coated tablets (containing trace amounts of glucose), and group C took prescription drugs with glucose an ingredient. Visual scores and quantitative variables with standard uptake value (SUV) for the brain, myocardium, blood, liver, and muscle in the FDG-PET images were analysed and statistically compared across the three groups. Results In group C, the amount of glucose was 0.63 ± 0.86 g (maximum 4.9 g). For the visual scores, there were no significant differences among the three groups. For the quantitative variables, significant differences were present in the brain SUVmax, muscle SUVmean, brain/blood ratio, brain/liver ratio, and brain/muscle ratio. However, a multivariate analysis showed that the group indicator was not significantly associated with any of the quantitative variables. On the other hand, blood glucose was significantly associated with the visual and quantitative variables. In group C, the correlation coefficient between the amount of glucose and the blood glucose level, the visual scores and the quantitative variables were in the range of − 0.121 to 0.100 and were not significant. Conclusions There were no significant differences between glucose-containing medications before FDG-PET and the visual scores and quantitative variables for FDG-PET image. Several grams of glucose in drugs before FDG-PET can be ignored.

Computer-aided detection of bone metastasis in bone scintigraphy images using parallelepiped classification method Abstract Objective Accurate diagnosis of metastatic tissue on bone scintigraphy images is of paramount importance in making treatment decisions. Although several automated systems have developed, more and better interpretation methods are still being sought. In the present study, a new modality for bone metastasis detection from bone scintigraphy images using parallelepiped classification (PC) as method for mapping the radionuclide distribution is presented. Methods Bone scintigraphy images from 12 patients with bone metastases were analyzed using the parallelepiped classifier that generated color maps of scintigraphic images. Seven classes of radionuclide accumulation have been identified and fed into machine learning software. The accuracy of the proposed method was evaluated by statistical measurements in a confusion matrix. Overall accuracy, producer’s and user’s accuracies and κ coefficient were computed from each confusion matrix associated with the individual case. Results The results revealed that the method is sufficiently precise to differentiate the metastatic bone from normal tissue (overall classification accuracy = 87.58 ± 2.25% and κ coefficient = 0.8367 ± 0.0252). The maps are easier to read (due to better contrast) and can detect even slightest differences in accumulation levels among pixels. Conclusions In conclusion, these preliminary data suggest that bone scintigraphy combined with PC method could play an important role in the detection of bone metastasis, allowing for an easier but correct interpretation of the images, with effects on the diagnosis accuracy and decision making on the treatment to be applied.

18 F-FDG PET/CT in the evaluation of cartilaginous bone neoplasms: the added value of tumor grading Abstract Objectives Cartilaginous bone tumors represent a wide variety of neoplasms ranging from benign to extremely aggressive malignant lesions. Unlike other tumors, the biopsy cannot easily predict the histological grade, sometimes not allowing choosing the best therapeutic approach. The aim of the study was to evaluate the ability of 18F-FDG PET/CT to differentiate enchondroma from chondrosarcoma and to predict the histological grade as compared to biopsy. Methods 18F-FDG PET/CT of 95 patients with chondroid lesions were retrospectively evaluated. The best SUVmax cutoff to predict the post-surgical histological grade were correlated to those of biopsy and to several radiologic aggressiveness features, which were summarized in the parameter “Radiologic Aggressiveness Score” (AgSCORE). Results A concordance between the preoperative biopsy and the definitive histological grade was observed overall in 78.3% of patients, the lowest accuracy (58.6%) being in the identification of intermediate/high-grade chondrosarcoma (G2/G3). The best SUVmax cutoff was 2.6 to discriminate enchondroma vs. low-grade chondrosarcoma (sensitivity 0.68, specificity 0.86), 3.7 to differentiate low-grade vs. intermediate/high-grade chondrosarcoma (sensitivity 0.83, specificity 0.84) and 7.7 to differentiate intermediate/high-grade vs. dedifferentiated chondrosarcoma (sensitivity 0.92, specificity 0.9). The AgSCORE also showed a high accuracy to differentiate between G1 and G2/G3 chondrosarcoma (cutoff = 4; sensitivity 0.76; specificity 0.89). An even higher accuracy was observed in those cases in which both SUVmax and AgSCORE cutoff were concordant. Conclusions Results in this large series of patients suggest a potential role of 18F-FDG PET/CT for histological grading of cartilaginous tumors, thus helping the orthopedic surgeon towards the most appropriate surgical procedure.

A pitfall of white matter reference regions used in [ 18 F] florbetapir PET: a consideration of kinetics Abstract Objective Many studies have demonstrated the superiority of white matter (WM) reference regions (RR) in amyloid PET studies in comparison to cerebellar RR. However, the principle behind its improved measurement stability is yet to be elucidated. Our study aimed to determine the origin of WM stability; stability over cerebral blood flow and input function fluctuation or the greater statistical noise in the cerebellum due to its smaller size and its location in the axial periphery of the PET scanner bore. Methods We conducted simulations of [ \({}^{18}\) F] florbetapir using in-house program varying \(K_1\) and input function, and adding statistical noise. Results Our simulations revealed that WM RR were more susceptible to CBF variation and input function fluctuation than cerebellar RR. WM RR did not gave superior measurement stability unless cerebellar statistical noise exceeded 4.55 times that in WM, a figure often surpassed in traditional amyloid PET studies. The greater statistical noise in cerebellum is likely the etiology for improved measurement stability of WM RR. Conclusion A longitudinal [ \({}^{18}\) F] florbetapir PET study should be conducted with a long bore PET. It can also be hypothesized that a second scan with the cerebellum in the axial center of a 3D PET, using a cerebellar RR to calculate changes in tracer concentration may improve the measurement stability of longitudinal [ \({}^{18}\) F] florbetapir studies.

Manual on the proper use of yttrium-90-labeled anti-P-cadherin antibody injection for radionuclide therapy in clinical trials Abstract We present the guideline for use of yttrium-90-labeled anti-P-cadherin antibody injection for radionuclide therapy in clinical trials on the basis of radiation safety issues in Japan. This guideline was prepared by a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine. Treatment using yttrium-90-labeled anti-P-cadherin antibody injection in Japan should be carried out according to this guideline. Although this guideline is applied in Japan, the issues for radiation protection shown here are considered internationally useful as well. Only the original Japanese version is the formal document.

Clinical utility of the normal database of 123 I-iodoamphetamine brain perfusion single photon emission computed tomography for statistical analysis using computed tomography-based attenuation correction: a multicenter study Abstract Objectives We have established a common normal database (NDB) with applicability in multicenter settings for the statistical analysis of brain perfusion single photon emission computed tomography (SPECT) with triple energy window scatter correction, computed tomography-based attenuation correction (CTAC), and spatial resolution compensation. This study aimed to compare the CTAC normal database (CTAC-NDB) with conventional normal databases for the statistical analysis of 123I-iodoamphetamine (123I-IMP) brain perfusion SPECT at three institutions and to assess the clinical efficiency of CTAC-NDB. Methods We recruited 45 patients (26 men and 19 women; mean age, 74.2 ± 3.9 years; Mini-Mental State Examination score, 19.8 ± 6.1) with Alzheimer’s disease (AD, n = 26), dementia with Lewy bodies (DLB, n = 9), and mild cognitive impairment (n = 10) from three institutions. Three-dimensional stereotactic surface projection (3D-SSP) technique was used to analyze data obtained from the 123I-IMP brain perfusion SPECT images compared with both CTAC-NDB and conventional NDB. We visually assessed each 3D-SSP z score map to determine the changes in specific findings, such as AD/DLB pattern. Furthermore, the stereotactic extraction estimation analysis software was used to measure the regional z score severity and extent as a semiquantitative assessment. Results In the visual assessment, all cases exhibited clearer findings with CTAC-NDB than with conventional NDB in the parietotemporal association cortex as well as in the inferior temporal, frontal, and lateral occipital cortices. Contrarily, the findings from the medial cerebral regions, including the precuneus and the posterior cingulate, became indistinct in 71% of the cases and remained unchanged in 25% of the cases. In the semiquantitative analysis, a similar tendency was observed in the mean z score in the three institutions included in the study. Conclusion Using the CTAC-NDB, the findings in the vicinity of the cranium became increasingly clear, whereas those in the medial surface of the brain became less defined or remained unchanged. These findings were confirmed via a semiquantitative analysis. Moreover, similar changes in the reduction pattern were observed in the three institutions. Therefore, the new database with CTAC might be applicable in other institutions. Data collected in this study may serve as a CTAC-NDB.