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1.  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
2.  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
3.  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
4.  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
5.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  Prognostic values of initial responses to low-dose 131I-MIBG therapy in patients with malignant pheochromocytoma and paraganglioma 
Annals of Nuclear Medicine  2013;27(9):839-846.
We retrospectively examined whether or not initial responses of first low-dose 131I-meta-iodo-benzyl-guanidine radiotherapy (131I-MIBG therapy) in patients with malignant pheochromocytoma and paraganglioma had prognostic values.
Materials and methods
This study included 26 patients with malignant pheochromocytoma (n = 18) and paraganglioma (n = 8) who underwent the first 131I-MIBG therapy between October 2001 and September 2007. Based on the initial subjective, hormonal, scintigraphic, and objective responses to 131I-MIBG therapy, the responses were divided into progression disease (PD) and non-PD. We examined the following factors for prognostic significance: sex, age, disease, initial diagnosis (benign or malignant pheochromocytoma), hypertension, diabetes mellitus, palpitations, symptoms related to bone metastases, and number of low-dose 131I-MIBG therapy. Univariate Cox proportional regression analysis was used to identify prognostic factors for overall survival. Overall survival was analyzed by Kaplan–Meier method and the curves were compared using the log-rank test.
The median survival time was 56 months. In the follow-up period, 16 patients died from exacerbation of their diseases. Univariate analysis showed that the hormonal PD [hazard ratio (HR) 3.20, P = 0.034, confidence interval (CI) 1.09–9.93], objective PD (HR 11.89, P = 0.0068, CI 2.14–65.85), single-time 131I-MIBG therapy (HR 3.22, P = 0.020, CI 1.21–8.79), hypertension (HR 2.93, P = 0.044, CI 1.02–10.50), and symptoms related to bone metastases (HR 3.54, P = 0.023, CI 1.18–13.04) were bad prognostic factors for overall survival. Kaplan–Meier analysis demonstrated that the hormonal non-PD (P = 0.026), objective non-PD (P = 0.0002), multiple-time 131I-MIBG therapy (P = 0.013), and no symptom related to bone metastases (P = 0.024) were significantly associated with good prognosis. Overall survival rate was 70 and 50 % at 5 years from the initial diagnosis and from the first 131I-MIBG therapy, respectively.
The hormonal and objective responses to the first low-dose 131I-MIBG therapy as well as complication of hypertension and symptoms related to bone metastases may be prognostic factors in patients with malignant pheochromocytoma and paraganglioma.
PMCID: PMC4328134  PMID: 23864328
Malignant pheochromocytoma; Malignant paraganglioma; Low-dose of 131I-MIBG; Initial response; Radiotherapy
19.  Diagnostic usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the PET diagnosis of chest malignancies 
Annals of Nuclear Medicine  2013;27(9):808-821.
Although positron emission tomography (PET) using [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) is established as one of the first-choice imaging modalities in the diagnosis of chest malignancies, there are several problems to solve in clinical practice, such as false positive uptake in inflammatory diseases. The aim of this study was to evaluate the clinical usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the diagnosis of chest malignancies, in combination with 18F-FDG.
Fifty-nine cases (57 patients, 66 ± 12 years old) who consulted to our institution for the wish to receive differential diagnosis of chest diseases were included. Purpose of the studies were as follows: differential diagnosis of newly developed lung nodules, n = 22; newly developed mediastinal lesions, n = 20; and both, n = 17 (including lung cancer: n = 19, lymphoma: n = 1, other cancers: n = 2, sarcoidosis: n = 15, non-specific inflammation: n = 18, other inflammatory: n = 4, respectively). Whole-body static PET or PET/CT scan was performed 20 and 50 min after the IV injection of 11C-MeAIB and 18F-FDG, respectively.
11C-MeAIB uptake of malignant and benign lesions was statistically different both in pulmonary nodules (p < 0.005) and in mediastinal lesions (p < 0.0005). In visual differential diagnosis, 11C-MeAIB showed higher results (specificity: 73 %, accuracy: 81 %), compared to those in 18F-FDG (60, 73 %, respectively). In cases of sarcoidosis, 11C-MeAIB showed higher specificity (80 %) with lower uptake (1.8 ± 0.7) in contrast to the lower specificity (60 %) with higher uptake of 18F-FDG (7.3 ± 4.5).
11C-MeAIB PET/CT was useful in the differential diagnosis of pulmonary and mediastinal mass lesions found on CT. 11C-MeAIB PET or PET/CT showed higher specificity than that of 18F-FDG PET/CT in differentiating between benign and malignant disease. Our data suggest that the combination of 18F-FDG and 11C-MeAIB may improve the evaluation of chest lesions, when CT and 18F-FDG PET/CT are equivocal.
PMCID: PMC3830191  PMID: 23824782
Amino acid tracer; Methylaminoisobutyric acid; Fluorodeoxyglucose; Lung cancer; Lymphadenopathy; Positron emission tomography; Sarcoidosis
20.  Positron emission mammography (PEM): reviewing standardized semiquantitative method 
Annals of Nuclear Medicine  2013;27(9):795-801.
To validate semiquantitative analysis of positron emission mammography (PEM).
Fifty women with histologically confirmed breast lesions were retrospectively enrolled. Semiquantitative uptake values (4 methods), the maximum PEM uptake value (PUVmax), and the lesion-to-background (LTB) value (3 methods) were measured. LTB is a ratio of the lesion’s PUVmax to the mean background; LTB1, LTB2, and LTB3 (which were calculated on different background) were used to designate the three values measured. Interobserver reliability between two readers for PUVmax and the LTBs was tested using the interobserver correlation coefficient (ICC). The likelihood ratio test was used to evaluate the relationship between ICCs. Receiver operating characteristic (ROC) curves were calculated for all methods. Diagnostic accuracy in differentiating benign tissue from malignant tissue was compared between PUVmax and LTB1.
The ICC rate was 0.971 [95 % confidence interval (CI) 0.943–0.986] for PUVmax, 0.873 (95 % CI 0.758–0.935) for LTB1, 0.965 (95 % CI 0.925–0.983) for LTB2, and 0.895 (95 % CI 0.799–0.946) for LTB3. However, there were some technical difficulties in the practical use of LTB2 and LTB3. The likelihood ratio test between PUVmax and LTB1 was statistically significant (p < 0.001). ROC curves of the 4 methods had similar characteristics. The median PUVmax was 1.39 for benign lesions and 3.70 for malignant lesions. LTB1 was 1.92 for benign lesions and 4.78 for malignant lesions. Significant differences (p < 0.001) in both PUVmax and LTB1 were observed between groups.
Due to its simplicity and reproducibility, PUVmax is superior to LTB as an indicator for PEM in semiquantitative analysis.
PMCID: PMC3830195  PMID: 23818008
Lesion-to-background (LTB); Maximum PEM uptake value (PUVmax); Positron emission mammography (PEM); Semiquantitative analysis
21.  Impaired renal function is a major determinant of left ventricular diastolic dysfunction: assessment by stress myocardial perfusion imaging 
Annals of Nuclear Medicine  2013;27(8):729-736.
Relationships between myocardial scintigraphic parameters and renal function have not been fully determined. We investigated correlations between estimated glomerular filtration rate (eGFR) and left ventricular (LV) diastolic function using stress electrocardiographic (ECG)-gated myocardial single photon emission computed tomography (SPECT).
We enrolled 136 consecutive patients with suspected coronary artery disease (CAD) who were assessed using technetium-99m stress ECG-gated myocardial SPECT. We evaluated SPECT images using 17-segment defect scores graded on a 5-point scale, summed stress score, summed rest score and summed difference score (SDS). The parameters for assessing LV diastolic function were peak filling rate (PFR), 1/3 mean filling rate and time to peak filling. The CAD was defined as SDS ≥2. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m2. Patients were assigned to the following four groups (no CAD/no CKD: control group, n = 68; CAD/no CKD: CAD group, n = 24; no CAD/CKD: CKD group, n = 34; CAD/CKD: CAD + CKD group, n = 10).
The PFR was significantly impaired after stress in the CKD and CAD + CKD groups compared with controls (p < 0.001 for both). Furthermore, PFR at rest positively correlated with eGFR (r = 0.29, p < 0.001) and inversely correlated with SDS (r = −0.18, p < 0.05). Multivariate stepwise regression analysis independently associated eGFR with PFR (β coefficient = 0.260, p = 0.002).
Our data suggest that impaired renal function is a significant determinant of LV diastolic dysfunction in patients with suspected CAD.
PMCID: PMC3824632  PMID: 23712332
Chronic kidney disease; Estimated glomerular filtration rate; Coronary artery disease; Left ventricular diastolic function; Gated SPECT
22.  Improved reproducibility of simple quantitative indices from 99mTc-GSA liver functional imaging 
Annals of Nuclear Medicine  2013;27(5):487-491.
We evaluated intra- and interoperator reproducibilities in calculating the conventional indices HH15 and LHL15 from 99mTc-diethylenetriamine pentaacetic acid galactosyl human serum albumin (99mTc-GSA) scintigraphy, and proposed new, simple methods for the calculation of quantitative indices.
The results of 99mTc-GSA scintigraphy in 33 patients were retrospectively analyzed. Heart and liver ROIs were drawn manually to cover cardiac blood pool and entire liver, respectively, and HH15 and LHL15 were calculated. In addition, square regions of interest (ROIs) of fixed sizes were placed at the highest activity in blood pool and the liver. Using the square heart ROI, sHH15, an equivalent of HH15, was computed. Fractional liver uptake at 15 min (FLU15) was calculated using the square heart and liver ROIs. Intra- and interoperator reproducibilities, as well as correlation with Indocyanine green retention rate at 15 min (ICG R15), were assessed for these four indices by linear regression analysis.
Substantial intra- and interoperator variabilities were found for HH15 and LHL15. The correlation coefficients for intra- and interoperator comparisons were 0.884 and 0.869 for HH15, respectively, and 0.919 and 0.917 for LHL15, respectively. The use of square ROIs instead of hand-drawn ROIs improved reproducibility. The correlation coefficients for intra- and interoperator comparisons were 0.988 and 0.973 for sHH15, respectively, and 0.989 and 0.975 for FLU15, respectively. Correlation with ICG R15 was better for sHH15 (r = 0.619) and FLU15 (r = −0.656) than for HH15 (r = 0.439) and LHL15 (r = −0.490).
HH15 and LHL15 showed substantial intra- and interoperator variabilities, and the use of square ROIs are indicated to provide better reproducibility.
PMCID: PMC3672508  PMID: 23595899
99mTc-GSA; Quantitation; Region of interest; Reproducibility; Liver function
23.  Voxel-based analysis of 201Tl SPECT for grading and diagnostic accuracy of gliomas: comparison with ROI analysis 
Annals of Nuclear Medicine  2013;27(6):493-501.
The aim of this retrospective study was to assess the utility of a voxel-based analysis (VBA) method for 201Tl SPECT in glioma, compared to conventional ROI analysis.
We recruited 24 patients with glioma (high-grade 15; low-grade 9), for whom pre-operative 201Tl SPECT and MRI were performed. SPECT images were coregistered with MRI. The uptake ratio (UR) images of tumor to contralateral normal tissue were measured on early and delayed images, and the 201Tl retention index (RI) map was calculated from the early and delayed uptake ratio maps. In the ROI analysis, tumors were traced on a UR map, and the mean and maximal uptake ratio values on the early images were, respectively, defined as the mean and maximal UR. The mean and maximal RI values (mean and maximal RI) were calculated by division of the mean and maximal UR, respectively, on the delayed image by the mean and maximal UR on the early image. For the RI map calculated voxel by voxel, the maximal RI value was defined as VBA-RI. We evaluated sensitivity and accuracy of differential analysis with the mean and maximal UR, RI, and VBA-RI.
The high- and low-grade groups showed no significant difference in mean and maximal RI (0.98 ± 0.12 vs. 1.05 ± 0.09 and 0.98 ± 0.18 vs. 1.05 ± 0.14, respectively). The AUC and accuracy of the mean and maximal RI were 0.681 and 66.7 %, and 0.622 and 62.5 %, respectively. In contrast, VBA-RI was higher in high-grade than in low-grade glioma (1.69 ± 0.27 vs. 0.68 ± 0.66, p < 0.001). The AUC and accuracy of VBA-RI were 0.963 and 95.8 %, which are higher than those obtained for mean (p < 0.05) and maximal RI (p < 0.01). There was no significant difference in ROC between the VBA-RI and the mean UR (0.911, p = 0.456) and maximal UR (0.933, p = 0.639); however, the AUC, sensitivity, and diagnostic accuracy of VBA-RI were all higher than those of the mean and maximal UR.
The voxel-based analysis method of 201Tl SPECT may improve diagnostic performance for gliomas, compared with ROI analysis.
PMCID: PMC3713261  PMID: 23592309
201Tl SPECT; Glioma; Voxel-based analysis
24.  Assessment of lung toxicity caused by bleomycin and amiodarone by Tc-99m HMPAO lung scintigraphy in rats 
Annals of Nuclear Medicine  2013;27(7):592-599.
The purpose of the study was to determine the lung toxicity caused by amiodarone (AD) and bleomycin (BLM) in rats, by means of Tc-99m HMPAO lung scintigraphy.
Thirty albino rats were randomly divided into five groups. After AD or BLM was dissolved with isotonic saline (SF), a 0.5 ml solution was applied to the right bronchus via a catheter. Group 1 (n = 5 rats) received a single dose of AD, group 2 (n = 5) received two doses of AD, group 3 (n = 9) received BLM, group 4 (n = 3) received hydrochloric acid (HCl), and group 5 (n = 8) received SF. Rats in groups 1, 2, 3 and 5 were given 37 MBq Tc-99m HMPAO from the tail vein on days 7, 14, 21 and 28, and at 4 and 24 h in group 4. Static images of 10 min duration were obtained at 30 and 60 min by a double-headed gamma camera (Infinia, GE, Tirat Hacermel, Israel) on 256 × 256 matrix. Regular regions of interests were drawn over the right lung (RL), left lung (LL) and the liver (Li), and lung/liver (L/Li) ratios were calculated. After the scintigraphic imaging procedures were completed, rats were killed. Lung tissues were evaluated on a scale of (+) to (+++++) for edema, alveolar structural integrity and infiltration by inflammatory cells.
Groups 2 and 3 showed statistically significant differences in RL/Li and LL/Li ratios, whereby RL/Li was higher than LL/Li (p < 0.05). There were no significant differences in RL/Li and LL/Li ratios in group 5 (p > 0.05). In histopathological examination, minimal damage or artifacts were observed in group 5. In group 4, almost all pathological findings were present in the right lung. Statistically significant (p < 0.01) histological differences were found when groups 1 and 5 were compared. More significant (p < 0.001) pathological effects were noted when groups 2 and 3 were compared to both groups 5 and 1. Injury was more prominent in the lung tissues of the control rats that were given HCl. Increased RL/Li ratios and histopathological findings were consistent.
Tc-99m HMPAO lung scan are found to be useful in the identification of patients with lung toxicity. The simplicity of the procedure and lower radiation exposure are the advantages of Tc-99m HMPAO lung scan.
PMCID: PMC3742950  PMID: 23558450
Tc-99m HMPAO lung scintigraphy; Bleomycin; Amiodarone; Lung toxicity; Rat
25.  A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3′-iodophenoxy)quinazoline 
Annals of Nuclear Medicine  2013;27(5):431-443.
Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, radioiodinated 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) was reported to possess good characteristics as a tumor imaging agent. We have explored the feasibility of developing tumor diagnosis ligands superior to radioiodinated PHY.
New phenoxyquinazoline derivatives were designed with various side chains introduced to the 6th position of PHY. The IC50 values of the new derivatives to interrupt EGFR-TK phosphorylation were evaluated and compared to well-known EGFR-TK inhibitors. Tumor uptake studies of the new 125I-labeled derivatives were conducted with A431 tumor-bearing mice. Selectivity and binding characteristics were analyzed by in vitro blocking studies and a binding assay. Furthermore, SPECT/CT scans were performed using A431 tumor-bearing mice.
Six quinazoline derivatives were designed and synthesized, and among these, 6a–d were found to have relatively high EGFR-TK inhibitory potency. In tumor uptake studies, [125I]6a ([125I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [125I]PYK was rapidly cleared from peripheral tissues, resulting in a high tumor-to-tissue ratio 24 h after injection. Moreover, the EGFR-TK selectivity of [125I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [125I]PYK provided clear SPECT images of tumors.
Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [125I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [125I]PYK suggest that the 123I-labeled counterpart, [123I]PYK, would have great potential for diagnostic SPECT tumor imaging.
PMCID: PMC3672506  PMID: 23494210
EGF; Radiopharmaceutical; SPECT; Tyrosine kinase; Quinazoline; Radioiodine

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