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1.  The effect of metal artefact reduction on CT-based attenuation correction for PET imaging in the vicinity of metallic hip implants: A phantom study 
Annals of nuclear medicine  2014;28(6):540-550.
To determine if metal artefact reduction (MAR) combined with a priori knowledge of prosthesis material composition can be applied to obtain CT-based attenuation maps with sufficient accuracy for quantitative assessment of 18F-fluorodeoxyglucose uptake in lesions near metallic prostheses.
A custom hip prosthesis phantom with a lesion-sized cavity filled with 0.2 ml 18F-FDG solution having an activity of 3.367 MBq adjacent to a prosthesis bore was imaged twice with a chrome-cobalt steel hip prosthesis and a plastic replica, respectively. Scanning was performed on a clinical hybrid PET/CT system equipped with an additional external 137Cs transmission source. PET emission images were reconstructed from both phantom configurations with CT-based attenuation correction (CTAC) and with CT-based attenuation correction using MAR (MARCTAC). To compare results with the attenuation-correction method extant prior to the advent of PET/CT, we also carried out attenuation correction with 137Cs transmission-based attenuation correction (TXAC). CTAC and MARCTAC images were scaled to attenuation coefficients at 511 keV using a tri-linear function that mapped the highest CT values to the prosthesis alloy attenuation coefficient. Accuracy and spatial distribution of the lesion activity was compared between the three reconstruction schemes.
Compared to the reference activity of 3.37 MBq, the estimated activity quantified from the PET image corrected by TXAC was 3.41 MBq. The activity estimated from PET images corrected by MARCTAC was similar in accuracy at 3.32 MBq. CTAC corrected PET images resulted in nearly 40% overestimation of lesion activity at 4.70 MBq. Comparison of PET images obtained with the plastic and metal prostheses in place showed that CTAC resulted in a marked distortion of the 18F-FDG distribution within the lesion, whereas application of MARCTAC and TXAC resulted in lesion distributions similar to those observed with the plastic replica.
MAR combined with a tri-linear CT number mapping for PET attenuation correction resulted in estimates of lesion activity comparable in accuracy to that obtained with 137Cs transmission-based attenuation correction, and far superior to estimates made without attenuation correction or with a standard CT attenuation map. The ability to use CT images for attenuation correction is a potentially important development because it obviates the need for a 137Cs transmission source, which entails extra scan time, logistical complexity and expense.
PMCID: PMC4101148  PMID: 24710757
PET/CT; attenuation correction; metal artefacts; metal artefact reduction; phantoms
2.  The clinical safety, biodistribution and internal radiation dosimetry of flutemetamol (18F) injection in healthy Japanese adult volunteers 
Annals of Nuclear Medicine  2015;29(7):627-635.
The Phase I safety, biodistribution and internal radiation dosimetry study in adult healthy Japanese males of flutemetamol (18F) injection, an in vivo β-amyloid imaging agent, is reported and compared with previously obtained Caucasian data.
Whole-body PET scans of 6 healthy volunteers (age 51.8–61.7 years) were acquired approximately 4 h post-injection (administered activity 102–160 MBq). Venous blood sampling determined 18F activity concentrations in whole blood and plasma and high-performance liquid chromatography (HPLC) established the percentages of parent [18F]flutemetamol and its metabolites. Voided urine activity was recorded. The decay-corrected and normalised 18F activity of 14 source organ regions as a function of time was entered into the OLINDA/EXM software to calculate the internal radiation dosimetry and effective dose of each subject following the MIRD schema. The pharmacokinetics, biodistribution and dosimetry profiles were compared to data obtained from a cohort of healthy Caucasian adult volunteers from a previous Phase I study of [18F]flutemetamol.
Flutemetamol (18F) injection was well tolerated. The highest mean initial uptakes were measured in the liver (15.2 %), lungs (10.2 %) and brain (6.6 %). The highest mean radiation absorbed doses were received by the gallbladder wall (366 μGy/MBq), upper large intestine (138 μGy/MBq) and small intestine (121 μGy/MBq). The mean effective dose was 34.9 μSv/MBq. HPLC analysis demonstrated that at 5-min post-injection about 75 % of plasma 18F radioactivity was in the form of parent [18F]flutemetamol, reducing to 8 and 2 % at 25 and 90 min, respectively, giving rise to less lipophilic 18F-labelled metabolites. Comparisons with the Caucasian cohort showed no differences that could be regarded as clinically significant.
The clinical safety of [18F]flutemetamol demonstrated no differences of clinical significance in the pharmacokinetics, biodistribution and internal radiation dosimetry profiles between Caucasian and Japanese adults.
PMCID: PMC4526582  PMID: 26044876
Amyloid imaging; [18F]Flutemetamol; PET; Biodistribution; Dosimetry; Healthy Japanese subjects
3.  Evaluation of the therapeutic efficacy of a MEK inhibitor (TAK-733) using 18F-fluorodeoxyglucose-positron emission tomography in the human lung xenograft model A549 
Annals of Nuclear Medicine  2015;29(7):613-620.
The aim of this study was to evaluate the potential of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.
TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5 % w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose). Tumor size was measured before treatment (day 0), and on days 1, 3, 7, 9, 11, and 14. PET scans were performed pretreatment (day 0), and on days 2, 4, 7, 10, and 14. Tracer accumulations in tumor tissue were quantified as the mean standard uptake value (SUVmean).
No deaths or treatment-related body weight losses occurred during the study period. TAK-733 showed dose-dependent inhibition of tumor growth and 18F-FDG uptake in tumor tissue. At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05). Tumor growth was inhibited in the 10 mg/kg group with a treated/control value of 31 % on day 14. The SUVmean on day 2 in this dosage group was statistically lower than that observed on day 0, and that seen in the vehicle group on day 2 (P < 0.05 for both comparisons). Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time. In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time.
18F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.
PMCID: PMC4526591  PMID: 26014721
TAK-733; 18F-FDG-PET; MEK inhibitor; A549 xenograft rat
4.  Impact of FDG-PET findings on decisions regarding patient management strategies: a multicenter trial in patients with lung cancer and other types of cancer 
Annals of Nuclear Medicine  2015;29(5):431-441.
To date, numerous studies have been conducted on the diagnostic capabilities of positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET). However, no studies designed to evaluate the influence of FDG-PET on the selection of patient management strategies within the Japanese healthcare system have been reported to date. The aim of the present study was to investigate prospectively the proportion of patients whose management strategies were modified based on FDG-PET findings (strategy modification rate).
The strategy modification rate was calculated by comparing the patient management strategy (test and treatment plans) after FDG-PET with the strategy before FDG-PET for 560 cancer patients with nine types of cancer (lung cancer, breast cancer, colorectal cancer, head/neck cancer, brain tumor, pancreas cancer, malignant lymphoma, cancer of unknown origin, and melanoma). In addition, the details of the modifications to the patient management strategies were analyzed.
The strategy modification rate for patients with lung cancer was 71.6 % (149 of 208 patients, 95 % confidence interval 65.0–77.7 %), which was higher than previously reported strategy modification rates for lung cancer before and after FDG-PET (25.6 %). The strategy modification rates for patients with cancers other than lung cancer were as follows: breast, 44.4 % (56/126); colorectal, 75.6 % (62/82); head and neck, 65.2 % (15/23); malignant lymphoma, 70.0 % (35/50); pancreas, 85.0 % (17/20); and cancer of unknown origin, 78.0 % (32/41). The mean modification rate (major and minor modifications) of the treatment plans after FDG-PET, relative to the plans before FDG-PET, was 55.4 % (range 44.0–69.2 %), with major modifications pertaining to the treatment plan made in 43.3–68.2 % of the patients based on the objectives of the FDG-PET examination.
The results from this study indicate that FDG-PET can contribute to the modification of management strategies (particularly treatment plans), especially for lung cancer patients but also for patients with other types of cancer.
PMCID: PMC4481297  PMID: 25812534
FDG-PET; Patient management strategy; Comparison between pre- and post-test periods; Lung cancer
5.  Comparison of 11C-4′-thiothymidine, 11C-methionine, and 18F-FDG PET/CT for the detection of active lesions of multiple myeloma 
Annals of Nuclear Medicine  2014;29(3):224-232.
The aims of this study were to evaluate the possibility of using 11C-methionine (11C-MET) and 11C-4′-thiothymidine (11C-4DST) whole-body PET/CT for the imaging of amino acid metabolism and DNA synthesis, respectively, when searching for bone marrow involvement in patients with multiple myeloma (MM) and to compare these findings with those for 18F-FDG PET/CT and aspiration cytology.
A total of 64 patients with MM, solitary plasmacytoma, monoclonal gammopathy of undetermined significance, or an unspecified diagnosis were prospectively enrolled. All the patients underwent three whole-body PET/CT examinations within a period of 1 week. First, the tracer accumulation was visually evaluated as positive, equivocal, or negative for 55 focal lytic lesions visualized using CT in 24 patients. Second, the percentages of marrow plasma cells as calculated using a bone marrow aspiration smear and tracer accumulation were evaluated in the posterior iliac crests of 36 patients.
Among the 55 lytic lesions, the 11C-MET and 11C-4DST findings tended to reveal more positive findings than the 18F-FDG findings. Based on the standard criteria for the diagnosis of active myeloma using the percentage of marrow plasma cells, significant differences were found between the 18F-FDG and 11C-MET findings and between the 18F-FDG and 11C-4DST findings, but no significant difference was observed between the 11C-MET and 11C-4DST findings.
The addition of 11C-MET and 11C-4DST to 18F-FDG when performing PET/CT enabled clearer evaluations of equivocal lesions. Based on cytological diagnostic criteria, 11C-MET and 11C-4DST were more sensitive than 18F-FDG for the detection of active lesions. 11C-MET and 11C-4DST were more useful than 18F-FDG for the detection of active lesions, especially during the early stage of disease.
PMCID: PMC4385147  PMID: 25421383
FDG; Methionine; 11C-4′-thiothymidine; PET/CT; Multiple myeloma
6.  Grading obstructive lung disease using tomographic pulmonary scintigraphy in patients with chronic obstructive pulmonary disease (COPD) and long-term smokers 
Annals of Nuclear Medicine  2014;29:91-99.
The severity of chronic obstructive lung disease (COPD) is defined by the degree of flow limitation measured as forced expiratory volume in 1 s, which mainly reflects impairment of large and intermediate airways. However, COPD is primarily a small airways disease. Therefore, better diagnostic tools are needed. Ventilation-Perfusion (V/P) SPECT is a sensitive method to detect obstructive lung changes but criteria for staging airway obstruction are missing.
To define and validate criteria to stage COPD using V/P SPECT.
74 subjects (healthy non-smokers, healthy smokers or with stable COPD) were included. All were examined with V/P SPECT in a hybrid SPECT/CT system. Spirometry was performed and patients were evaluated with the clinical COPD questionnaire (CCQ). V/P SPECT was interpreted independently. Preserved lung function (%) was evaluated. The degree of airway obstruction on V/P SPECT was graded according to newly-developed grading criteria. The degree of airway obstruction was graded from normal (0) to severe (3). The airway obstructivity-grade and degree of preserved lung function were compared to GOLD, CCQ and LDCT emphysema extent.
Obstructivity-grade (r = 0.66, P < 0.001) and the degree of preserved lung function (r = −0.70, P < 0.001) both correlated to GOLD. Total preserved lung function decreased in relation to higher GOLD stage. There was a significant difference between healthy controls and apparently healthy long time smokers both regarding obstructivity-grade (P = 0.001) and preserved lung function (P < 0.001). Long-time smokers did not differ significantly from GOLD 1 COPD patients (P = 0.14 and P = 0.55 for obstructivity-grade and preserved lung function, respectively). However, patients in GOLD 1 differed in obstructivity-grade from non-smoking controls (P = 0.02).
Functional imaging with V/P SPECT enables standardized grading of airway obstruction as well as reduced lung function, both of which correlate with GOLD stage. V/P SPECT shows that long-term smokers in most cases have signs of ventilatory impairment and airway obstruction not shown by spirometry.
PMCID: PMC4284371  PMID: 25315109
Ventilation/Perfusion SPECT; Pulmonary scintigraphy; Chronic obstructive pulmonary disease (COPD); Imaging interpretation criteria; Technegas
7.  Detailed assessment of gene activation levels by multiple hypoxia-responsive elements under various hypoxic conditions 
Annals of Nuclear Medicine  2014;28(10):1011-1019.
HIF-1/HRE pathway is a promising target for the imaging and the treatment of intractable malignancy (HIF-1; hypoxia-inducible factor 1, HRE; hypoxia-responsive element). The purposes of our study are: (1) to assess the gene activation levels resulting from various numbers of HREs under various hypoxic conditions, (2) to evaluate the bidirectional activity of multiple HREs, and (3) to confirm whether multiple HREs can induce gene expression in vivo.
Human colon carcinoma HCT116 cells were transiently transfected by the constructs containing a firefly luciferase reporter gene and various numbers (2, 4, 6, 8, 10, and 12) of HREs (nHRE+, nHRE−). The relative luciferase activities were measured under various durations of hypoxia (6, 12, 18, and 24 h), O2 concentrations (1, 2, 4, 8, and 16 %), and various concentrations of deferoxamine mesylate (20, 40, 80, 160, and 320 µg/mL growth medium). The bidirectional gene activation levels by HREs were examined in the constructs (dual-luc-nHREs) containing firefly and Renilla luciferase reporter genes at each side of nHREs. Finally, to test whether the construct containing 12HRE and the NIS reporter gene (12HRE-NIS) can induce gene expression in vivo, SPECT imaging was performed in a mouse xenograft model.
(1) gene activation levels by HREs tended to increase with increasing HRE copy number, but a saturation effect was observed in constructs with more than 6 or 8 copies of an HRE, (2) gene activation levels by HREs increased remarkably during 6–12 h of hypoxia, but not beyond 12 h, (3) gene activation levels by HREs decreased with increasing O2 concentrations, but could be detected even under mild hypoxia at 16 % O2, (4) the bidirectionally proportional activity of the HRE was confirmed regardless of the hypoxic severity, and (5) NIS expression driven by 12 tandem copies of an HRE in response to hypoxia could be visualized on in vivo SPECT imaging.
The results of this study will help in the understanding and assessment of the activity of multiple HREs under hypoxia and become the basis for hypoxia-targeted imaging and therapy in the future.
PMCID: PMC4483249  PMID: 25249501
Hypoxia-responsive element (HRE); Reporter genes; Tumor hypoxia; Molecular imaging; Gene therapy
8.  Lesion-based analysis of 18F-FDG uptake and 111In-Pentetreotide uptake by neuroendocrine tumors 
Annals of Nuclear Medicine  2014;28(10):1004-1010.
To characterize the heterogeneity of metastatic neuroendocrine tumor (NET) lesions, we compared the [18F]-fluorodeoxyglucose (FDG) uptake and the 111In-pentetreotide (SRS) uptake for somatostatin receptor scintigraphy using the CT-based fusion imaging techniques of PET/CT and SPECT/CT.
Fifteen consecutive patients with NET lesions were examined using both FDG-PET/CT and SRS SPECT/CT prospectively. A total of 45 metastatic NET lesions were evaluated for FDG uptake according to the standardized uptake value (SUV) and for SRS uptake according to the tumor-to-muscle count ratio (T/M ratio); these values were then compared according to the grade of NET (G), also compared to the tumor volume.
Both the SRS uptake and FDG uptake showed no significant correlation to the tumor volume, and suggested no significant artifacts in these data. The T/M ratio for the SRS uptake ranged from 192.7 to 1.9 and exhibited very wide range of distribution. The SUV for the FDG uptake ranged from 13.8 to 0.77 and exhibited narrow range of distribution. The uptake of the two tracers in individual lesions showed an inverse correlation. The G1 + 2 lesions had a higher SRS uptake than the G3 lesions, but the difference was not significant because of the large variation (40.65 ± 48.03, n = 39 vs. 8.66 ± 13.13, n = 6). However, the G1 + 2 lesions had a significantly lower FDG uptake than the G3 lesions (3.52 ± 1.84, n = 39 vs. 10.82 ± 4.50, n = 6). The tracer uptakes varied largely not only in an inter-subject manner, but also in an intra-subject manner.
An inverse correlation between SRS uptake and FDG uptake in the metastatic NET lesions observed in this study may be consistent with the opposing ideas of differentiation and proliferation in oncology. The large variations in SRS and FDG uptake by metastatic NET lesions suggest the biological heterogeneity of advanced NET. These results support the idea that combination therapy targeting both receptor-positive cells and proliferating cells may be beneficial from a functional imaging perspective.
PMCID: PMC4244561  PMID: 25179521
18F-fluorodeoxyglucose; FDG; Positron Emission Tomography (PET); 111In-pentetreotide; Somatostatin receptor scintigraphy; Neuroendocrine tumor; Tumor heterogeneity
9.  68Gallium- and 90Yttrium-/177Lutetium: “theranostic twins” for diagnosis and treatment of NETs 
Abundant expression of somatostatin receptors (SSTR) is frequently identified in differentiated neuroendocrine tumors and may serve as potential target for diagnostic imaging and treatment. This article discusses the “theranostic approach” of SSTR-targeting compounds including an overview of its role for diagnosis, staging and restaging, discussing its way to being established in clinical routine, and giving an outlook about further potentially relevant developments.
PMCID: PMC4306729  PMID: 25139472
Neuroendocrine tumor; Theranostic; SPECT/CT; PET/CT; PRRT; Radionuclide therapy
10.  Evaluation of regional cerebral glucose metabolism in patients with malignant lymphoma of the body using statistical image analysis 
Annals of Nuclear Medicine  2014;28(10):950-960.
The aim of this study was to clarify the characteristics of regional cerebral glucose metabolic abnormalities in patients with malignant lymphoma of the body using statistical image analyses. Post-therapeutic changes in cerebral glucose metabolism were also evaluated.
The subjects consisted of 30 patients, including 16 patients with diffuse large B-cell lymphoma and 14 patients with other types of lymphoma. Patients with primary cerebral lymphoma were excluded from this study. All patients underwent CT and whole-body FDG-PET scans, including 4-min brain scans using a dedicated PET/CT scanner during both the pre- and post-treatment periods. The whole-body scans started 60 min after the administration of 185 MBq of FDG, after which the brain data were extracted from whole-body data. The degree of regional cerebral glucose metabolism was evaluated on a voxel-by-voxel basis using statistical parametric mapping (SPM). The total tumor glycolytic volume of the body was measured using a separate workstation. The normal control subjects were 12 persons who underwent medical check with FDG-PET/CT and had no lesions suggesting malignant tumor.
The level of regional cerebral glucose metabolism decreased in association with an increase in the total glycolytic volume in the bilateral frontal and parietal cortices. After chemotherapy, the statistical image analysis demonstrated an interval recovery of the cerebral glucose metabolism of the bilateral parietal and occipital cortices in the good responders, whereas there were no significant differences observed in regional cerebral glucose metabolism between the pre- and post-treatment images in the poor responders. Comparison between normal control subjects and patients with pre-treatment lymphoma also showed that the regional cerebral glucose metabolism decreased in the parieto-occipital cortices in patients with lymphoma compared to normal control subjects.
We demonstrated that patients with malignant lymphoma of the body exhibited abnormal regional cerebral glucose metabolism, which improves after chemotherapy. Although the mechanism underlying the reduction of cerebral glucose metabolism remains unclear, our findings indicate the functional alternation and/or subclinical damage of the brain in patients with malignant lymphoma.
PMCID: PMC4244549  PMID: 25113148
Malignant lymphoma; FDG-PET/CT; Paraneoplastic syndrome; Regional cerebral glucose metabolism; Statistical image analysis
11.  Ultrahigh-resolution Cerenkov-light imaging system for positron radionuclides: potential applications and limitations 
Annals of Nuclear Medicine  2014;28(10):961-969.
Cerenkov-light imaging provides inherently high resolution because the light is emitted near the positron radionuclide. However, the magnitude for the high spatial resolution of Cerenkov-light imaging is unclear. Its potential molecular imaging applications also remain unclear. We developed an ultrahigh-resolution Cerenkov-light imaging system, measured its spatial resolution, and explored its applications to molecular imaging research.
Our Cerenkov-light imaging system consists of a high-sensitivity charged-coupled device camera (Hamamatsu Photonics ORCA2-ER) and a bright lens (Xenon 0.95/25). An extension ring was inserted between them to magnify the subject. A ~100-μm-diameter 22Na point source was made and imaged by the system. For applications of Cerenkov-light imaging, we conducted 18F-FDG administered in vivo, ex vivo whole brain, and sliced brain imaging of rats.
We obtained spatial resolution of ~220 μm for a 22Na point source with our developed imaging system. The 18F-FDG rat head images showed high light intensity in the eyes for the Cerenkov-light images, although there was no accumulation in these parts in the PET images. The sliced rat brain showed much higher spatial resolution for the Cerenkov-light images compared with CdWO4 scintillator-based autoradiography, although some contrast decrease was observed for them.
Even though the Cerenkov-light images showed ultrahigh resolution of ~220 μm, their distribution and contrast were sometimes different from the actual positron accumulation in the subjects. Care must be taken when evaluating positron distribution from Cerenkov-light images. However, the ultrahigh resolution of Cerenkov-light imaging will be useful for transparent subjects including phantom studies.
PMCID: PMC4483184  PMID: 25103137
Cerenkov-light imaging; Ultrahigh resolution; CCD camera; Positron; Molecular imaging
12.  Quantitative assessment of rest and acetazolamide CBF using quantitative SPECT reconstruction and sequential administration of 123I-iodoamphetamine: comparison among data acquired at three institutions 
Annals of Nuclear Medicine  2014;28(9):836-850.
A recently developed technique which reconstructs quantitative images from original projection data acquired using existing single-photon emission computed tomography (SPECT) devices enabled quantitative assessment of cerebral blood flow (CBF) at rest and after acetazolamide challenge. This study was intended to generate a normal database and to investigate its inter-institutional consistency.
The three institutions carried out a series of SPECT scanning on 32 healthy volunteers, following a recently proposed method that involved dual administration of 123I-iodoamphetamine during a single SPECT scan. Intra-institute and inter-institutional variations of regional CBF values were evaluated both at rest and after acetazolamide challenge. Functional images were pooled for both rest and acetazolamide CBF, and inter-institutional difference was evaluated among these images using two independent software programs.
Quantitative assessment of CBF images at rest and after acetazolamide was successfully achieved with the given protocol in all institutions. Intra-institutional variation of CBF values at rest and after acetazolamide was consistent with previously reported values. Quantitative CBF values showed no significant difference among institutions in all regions, except for a posterior cerebral artery region after acetazolamide challenge in one institution which employed SPECT device with lowest spatial resolution. Pooled CBF images at rest and after acetazolamide generated using two software programs showed no institutional differences after equalization of the spatial resolution.
SPECT can provide reproducible images from projection data acquired using different SPECT devices. A common database acquired at different institutions may be shared among institutions, if images are reconstructed using a quantitative reconstruction program, and acquired by following a standardized protocol.
PMCID: PMC4244544  PMID: 25001261
Single-photon emission computed tomography; Cerebral blood flow; Cerebral vascular disease; Kinetic modeling; Ischemia
14.  Japanese guideline for the oncology FDG-PET/CT data acquisition protocol: synopsis of Version 2.0 
Annals of Nuclear Medicine  2014;28(7):693-705.
This synopsis outlines the Japanese guideline Version 2.0 for the data acquisition protocol of oncology FDG-PET/CT scans that was created by a joint task force of the Japanese Society of Nuclear Medicine Technology, the Japanese Society of Nuclear Medicine and the Japanese Council of PET Imaging, and was published in Kakuigaku-Gijutsu 2013; 33:377–420 in Japanese. The guideline aims at standardizing the PET image quality among PET centers and different PET camera models by providing criteria for the IEC body phantom image quality as well as for the patient PET image quality based on the noise equivalent count (NEC), NEC density and liver signal-to-noise ratio, so that the appropriate scanning parameters can be determined for each PET camera. This Version 2.0 covers issues that were not focused on in Version 1.0, including the accuracy of the standardized uptake value (SUV), effect of body size together with adjustment of scanning duration, and time-of-flight (TOF) reconstruction technique. Version 2.0 also presents data acquired with new PET camera models that were not tested in Version 1.0. Reference values for physical indicators of phantom image quality have been updated as well.
PMCID: PMC4332454  PMID: 24859759
Guideline; FDG-PET; Oncology; Noise equivalent count; Phantom
15.  A Hand-Held Beta Imaging Probe for FDG 
Annals of nuclear medicine  2012;27(3):203-208.
Advances in radiopharmaceuticals and clinical understanding have escalated the use of intraoperative gamma probes in surgery. However, most probes on the market are non-imaging gamma probes that suffer from the lack of ancillary information of the surveyed tissue area. We have developed a novel, hand-held digital Imaging Beta Probe™ (IBP™) to be used in surgery in conjunction with beta-emitting radiopharmaceuticals such as 18FDG, 131I and 32P for real-time imaging of a surveyed area with higher spatial resolution and sensitivity and greater convenience than existing instruments.
We describe the design and validation of a hand-held beta probe intended to be used as a visual mapping device to locate and confirm excision of 18FDG-avid primary tumors and metastases in an animal model.
We have demonstrated a device which can generate beta images from 18FDG avid lesions in an animal model.
It is feasible to image beta irradiation in animal models of cancer given 18FDG. This technology may be applied to clinical mapping of tumors and/or their metastases in the operating room. Visual image depiction of malignancy may aid the surgeon in localization and excision of lesions of interest.
PMCID: PMC3622128  PMID: 23229110
18FDG; PET; 131I; Imaging; Beta Probe
16.  Japanese consensus guidelines for pediatric nuclear medicine 
Annals of Nuclear Medicine  2014;28(5):498-503.
The Japanese Society of Nuclear Medicine has recently published the consensus guidelines for pediatric nuclear medicine. This article is the English version of the guidelines. Part 1 proposes the dose optimization in pediatric nuclear medicine studies. Part 2 comprehensively discusses imaging techniques for the appropriate conduct of pediatric nuclear medicine procedures, considering the characteristics of imaging in children.
PMCID: PMC4061477  PMID: 24647992
17.  Yttrium-90 distribution following radiosynoviorthesis of the knee joint in rheumatoid arthritis patients: a SPECT/CT study 
Annals of Nuclear Medicine  2014;28(7):688-692.
To examine yttrium-90 distribution 1 and 72 h following its injection into a knee joint in patients with rheumatoid arthritis (RA).
In 14 RA patients we injected yttrium-90 into the affected knee joint using lateral approach. To assess the radioisotope distribution in the joint, the superimposed sequential SPECT and CT imaging was performed 1 and 72 h after the injection. We analyzed the percentage of radioisotope distribution in three predefined compartments of the knee joint (lower, upper medial, upper lateral).
After 1 and 72 h, the mean percentage distributions were, respectively, 7.14 and 23.07 % in lower; 21.42 and 15.38 % in upper medial, and 71.42 and 61.53 % in upper lateral compartment. The percentage of isotope deposition did not change significantly with time in any of the compartments (all p > 0.26). The deposition of isotope, both at 1 and 72 h, was significantly greater in upper lateral compartment, where the injection was performed, than in all other compartments (all p < 0.05).
Using the SPECT/CT hybrid method, we proved that the majority of isotope is located at the compartment adjacent to the injection. Two injections targeting different compartments might improve the clinical efficacy of the procedure.
PMCID: PMC4135179  PMID: 24595462
Rheumatoid arthritis; Radiosynoviorthesis; Yttrium-90 isotope; SPECT/CT
18.  Evaluation of the difference-correction effect of the gamma camera systems used by easy Z-score Imaging System (eZIS) analysis 
Annals of Nuclear Medicine  2014;28(3):263-275.
We examined the difference of the effect by data to revise a gamma camera difference. The difference-correction method of the camera is incorporated in eZIS analysis.
We acquired single photon emission computed tomography (SPECT) data from the three-dimensional (3D) Hoffman brain phantom (Hoffman), the three-dimensional brain phantom (3D-Brain), Pool phantom (pool) and from normal subjects (Normal-SPECT) to investigate compensating for a difference in gamma camera systems. We compared SPECT counts of standard camera with the SPECT counts that revised the difference of the gamma camera system (camera). Furthermore, we compared the “Z-score map (Z-score)”. To verify the effect of the compensation, we examined digitally simulated data designed to represent a patient with Alzheimer’s dementia. We carried out both eZIS analysis and “Specific Volume of interest Analysis (SVA)”.
There was no great difference between the correction effect using Hoffman phantom data and that using 3D-Brain phantom data. Furthermore, a good compensation effect was obtained only over a limited area. The compensation based on the pool was found to be less satisfactory than any of the other compensations according to all results of the measurements examined in the study. The compensation based on the Normal-SPECT data resulted in a Z-score map (Z-score) for the result that approximated that from the standard camera. Therefore, we concluded that the effect of the compensation based on Normal-SPECT data was the best of the four methods tested.
Based on eZIS analysis, the compensation using the pool data was inferior to the compensations using the other methods tested. Based on the results of the SAV analysis, the effect of the compensation using the Hoffman data was better than the effect of the compensation using the 3D-Brain data. By all end-point measures, the compensation based on the Normal-SPECT data was more accurate than the compensation based on any of the other three phantoms.
PMCID: PMC3988514  PMID: 24464392
99mTc-ECD; 99mTc-HMPAO; SPM; eZIS; Image correction
19.  Lung uptake on I-131 therapy and short-term outcome in patients with lung metastasis from differentiated thyroid cancer 
Annals of Nuclear Medicine  2013;28(2):81-87.
It is sometimes difficult to assess I-131 lung uptake at the initial I-131 therapy because of strong artifacts from I-131 uptake in the thyroid bed. The aim of this study was to analyze the lung uptake at the second I-131 therapy for lung metastasis in patients who did not have lung uptake at the initial therapy from differentiated thyroid carcinoma (DTC). Then, we also analyzed the relationship between the initial lung uptake and short-term outcome after I-131 therapies.
This study included 62 DTC patients with lung metastasis. The patients were classified into 2 groups according to the lung uptake at the initial I-131 therapy such as patients with lung uptake (positive uptake group n = 31) and those without lung uptake (negative uptake group n = 31). The lung uptake was analyzed at the second therapy in both groups. The short-term outcome was also analyzed based on the CT findings of lung metastasis size and serum thyroglobulin level between the two groups.
The positive uptake group showed positive lung uptake at the second therapy in 23 patients (74 %), whereas none of negative uptake group showed any lung uptake at the second therapy (P < 0.01). The positive uptake group significantly decreased in the size of lung metastasis from the initial therapy to the second therapy (20.0 ± 11.7 to 16.6 ± 9.6 mm, P < 0.01) with further decrease after the second therapy (P < 0.05). The serum thyroglobulin level was also significantly decreased from the initial therapy to the second therapy (4348 ± 7011 to 2931 ± 4484 ng/ml, P < 0.05). In contrast, the negative uptake group significantly increased in the size of lung metastasis from the initial therapy to the second therapy (17.3 ± 12.2 to 19.9 ± 14.3 mm, P < 0.01) with further increase after the second therapy (P < 0.01).
No patients without lung uptake at the initial I-131 therapy showed lung uptake at the second therapy, or showed treatment effect. Therefore, second I-131 therapy for these patients with initially negative lung uptake should be considered cautiously.
PMCID: PMC3971446  PMID: 24374647
Thyroid cancer; Lung metastasis; I-131 therapy; Radioiodine therapy
20.  Diagnosis of dementia with Lewy bodies: diagnostic performance of combined 123I-IMP brain perfusion SPECT and 123I-MIBG myocardial scintigraphy 
Annals of Nuclear Medicine  2013;28(3):203-211.
We assessed the value of combining 123I-IMP brain perfusion SPECT and 123I-MIBG myocardial scintigraphy for the discrimination of dementia with Lewy bodies (DLB) from other types of dementia.
We subjected 252 consecutive patients with clinically suspected DLB to both 123I-IMP brain perfusion SPECT and 123I-MIBG myocardial scintigraphy. Patients with Parkinson’s disease were included. The 252 patients were randomly assigned to an estimation (n = 152) or a validation group (n = 100). Using univariate analysis, we first analyzed the relationship between various variables and the presence or absence of DLB in estimation group and then proceeded to multivariate analysis to obtain a combined index that predicted the likelihood of DLB. The diagnostic value of the index was assessed by calculating the area under the receiver operating characteristic (ROC) curve (AUC) with the cutoff value selected from the ROC curve. We then tested the predictive accuracy of the index in validation group.
The combined index was an arithmetic expression that combined the age, early 123I-MIBG heart-to-mediastinum uptake (E-H/M) ratio, and the parietal lobe hypoperfusion score. Values for the AUC of the combined index, the E-H/M ratio, the parietal lobe hypoperfusion score, and the patient age in validation group were 0.95, 0.90, 0.72, and 0.73, respectively. There was a significant difference in the AUC of the combined index among other indices (p < 0.05). The sensitivity, specificity, and accuracy of the combined index for a diagnosis of probable DLB in validation group were 88, 87, and 87 %, respectively.
The combinational diagnosis based on 123I-IMP brain perfusion SPECT, 123I-MIBG myocardial scintigraphy, and the patient age is a simple and reliable means for predicting probable DLB.
PMCID: PMC4483188  PMID: 24363079
Dementia with Lewy bodies; 123I-IMP brain perfusion SPECT; 123I-MIBG myocardial scintigraphy; Combined index
21.  Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with 99mTc-DTPA-glipizide 
Annals of nuclear medicine  2012;26(3):10.1007/s12149-011-0569-9.
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.
PMCID: PMC3865706  PMID: 22237676
99mTc-DTPA-glipizide; Sulfonylurea receptor; Imaging; Pancreas
22.  Clinical use of 11C-methionine and 18F-FDG-PET for germinoma in central nervous system 
Annals of Nuclear Medicine  2013;28(2):94-102.
The purpose of this study was to examine the 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) findings of central nervous system (CNS) germinoma and the diagnostic utility of these findings.
We retrospectively evaluated the cases of 10 patients who were diagnosed with CNS germinoma according to their histopathological or clinical findings. All the patients underwent pretreatment MET and/or FDG-PET scans, and the resultant images were assessed qualitatively and quantitatively. In the qualitative assessments, we used 3- and 5-grade visual scoring systems for the MET- and FDG-PET images, respectively. In the quantitative assessments, the maximal standardized uptake value (SUVmax) and the ratio of the SUVmax of the tumor (T) divided by the mean SUV for the normal white or gray matter [T/N (WM), T/N (GM)], was calculated.
The mean and SD values of SUVmax, T/N (WM), and T/N (GM) were 1.9 ± 1.4, 2.5 ± 1.3, and 1.7 ± 0.9 on MET-PET and 5.8 ± 2.2, 1.6 ± 0.5, and 0.8 ± 0.2 on FDG-PET, respectively. On MET-PET, only one lesion was not detected. On the other hand, on FDG-PET all of the lesions exhibited uptake values that were intermediate between those of the normal white matter and gray matter.
In terms of its tumor-contouring ability, MET is a good tracer for diagnosing CNS germinomas; therefore, MET-PET is considered to be useful for planning biopsies or surgery. Although FDG-PET is capable of detecting CNS germinomas, it produced insufficient image contrast in the present study. Further studies are needed before FDG-PET can be used in clinical examinations of CNS germinoma.
PMCID: PMC3926980  PMID: 24272066
Germinoma; Positron emission tomography; 11C-methionine; 18F-FDG
23.  Feasibility of deep-inspiration breath-hold PET/CT with short-time acquisition: detectability for pulmonary lesions compared with respiratory-gated PET/CT 
Annals of Nuclear Medicine  2013;28(1):1-10.
Deep-inspiration breath-hold (DIBH) PET/CT with short-time acquisition and respiratory-gated (RG) PET/CT are performed for pulmonary lesions to reduce the respiratory motion artifacts, and to obtain more accurate standardized uptake value (SUV). DIBH PET/CT demonstrates significant advantages in terms of rapid examination, good quality of CT images and low radiation exposure. On the other hand, the image quality of DIBH PET is generally inferior to that of RG PET because of short-time acquisition resulting in poor signal-to-noise ratio. In this study, RG PET has been regarded as a gold standard, and its detectability between DIBH and RG PET studies was compared using each of the most optimal reconstruction parameters.
In the phantom study, the most optimal reconstruction parameters for DIBH and RG PET were determined. In the clinical study, 19 cases were examined using each of the most optimal reconstruction parameters.
In the phantom study, the most optimal reconstruction parameters for DIBH and RG PET were different. Reconstruction parameters of DIBH PET could be obtained by reducing the number of subsets for those of RG PET in the state of fixing the number of iterations. In the clinical study, high correlation in the maximum SUV was observed between DIBH and RG PET studies. The clinical result was consistent with that of the phantom study surrounded by air since most of the lesions were located in the low pulmonary radioactivity.
DIBH PET/CT may be the most practical method which can be the first choice to reduce respiratory motion artifacts if the detectability of DIBH PET is equivalent with that of RG PET. Although DIBH PET may have limitations in suboptimal signal-to-noise ratio, most of the lesions surrounded by low background radioactivity could provide nearly equivalent image quality between DIBH and RG PET studies when each of the most optimal reconstruction parameters was used.
PMCID: PMC3892105  PMID: 24151087
Deep-inspiration breath-hold (DIBH) PET/CT; Respiratory-gated (RG) PET/CT; Pulmonary lesion; Reconstruction parameters
24.  Value of fusion of PET and MRI in the detection of intra-pelvic recurrence of gynecological tumor: comparison with 18F-FDG contrast-enhanced PET/CT and pelvic MRI 
Annals of Nuclear Medicine  2013;28(1):25-32.
To evaluate the diagnostic value of retrospective image fusion from pelvic magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (PET) in detecting intra-pelvic recurrence of gynecological tumor.
Thirty patients with a suspicion of recurrence of gynecological malignancy underwent inline contrast-enhanced PET/computed tomography (CT) and pelvic contrast-enhanced MRI for restaging. Diagnostic performance about the local recurrence, pelvic lymph node and bone metastasis and peritoneal lesion of PET/low-dose non-enhanced CT (PET/ldCT), PET/full-dose contrast-enhanced CT (PET/ceCT), contrast-enhanced MRI, and retrospective image fusion from PET and MRI (fused PET/MRI) were evaluated by two experienced readers. Final diagnoses were obtained by histopathological examinations, radiological imaging and clinical follow-up for at least 6 months. McNemar test was employed for statistical analysis.
Documented positive locally recurrent disease, pelvic lymph node and bone metastases, and peritoneal dissemination were present in 53.3, 26.7, 10.0, and 16.7 %, respectively. Patient-based sensitivity for detecting local recurrence, pelvic lymph node and bone metastasis and peritoneal lesion were 87.5, 87.5, 100 and 80.0 %, respectively, for fused PET/MRI, 87.5, 62.5, 66.7 and 60.0 %, respectively, for contrast-enhanced MRI, 62.5, 87.5, 66.7 and 80.0 %, respectively, for PET/ceCT, and 50.0, 87.5, 66.7 and 60.0 %, respectively, for PET/ldCT. The sensitivity of diagnosing local recurrence by fused PET/MRI was significantly better than that of PET/ldCT (p = 0.041). The patient-based sensitivity, specificity and accuracy for the detection of intra-pelvic recurrence/metastasis were 91.3, 100 and 93.3 % for fused PET/MRI, 82.6, 100 and 86.7 % for contrast-enhanced MRI, 82.6, 100 and 86.7 % for PET/ceCT and 78.3, 85.7 and 80.0 % for PET/ldCT.
Fused PET/MRI combines the individual advantages of MRI and PET, and is a valuable technique for assessment of intra-pelvic recurrence of gynecological cancers.
PMCID: PMC4328133  PMID: 24129541
Fused PET/MRI; PET/CT; MRI; Restaging; Gynecological tumor
25.  Prediction of outcomes in MCI with 123I-IMP-CBF SPECT: a multicenter prospective cohort study 
Annals of Nuclear Medicine  2013;27(10):898-906.
The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of 123I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI).
Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and 123I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline 123I-IMP-CBF SPECT was predictive of longitudinal clinical outcome.
Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08).
123I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.
Electronic supplementary material
The online version of this article (doi:10.1007/s12149-013-0768-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4328132  PMID: 24061691
Alzheimer’s disease; Mild cognitive impairment; SPECT; Cerebral blood flow; Prospective study

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