Search

This study aimed at demonstrating the feasibility of retrospectively fused (18)F FDG-PET and MRI (PET/MRI fusion image) in diagnosing pancreatic tumor, in particular differentiating malignant tumor from benign lesions. In addition, we evaluated additional findings characterizing pancreatic lesions by FDG-PET/MRI fusion image.We analyzed retrospectively 119 patients: 96 cancers and 23 benign lesions. FDG-PET/MRI fusion images (PET/T1 WI or PET/T2WI) were made by dedicated software using 1.5 Tesla (T) MRI image and FDG-PET images. These images were interpreted by two well-trained radiologists without knowledge of clinical information and compared with FDG-PET/CT images. We compared the differential diagnostic capability between PET/CT and FDG-PET/MRI fusion image. In addition, we evaluated additional findings such as tumor structure and tumor invasion.FDG-PET/MRI fusion image significantly improved accuracy compared with that of PET/CT (96.6 vs. 86.6 %). As additional finding, dilatation of main pancreatic duct was noted in 65.9 % of solid types and in 22.6 % of cystic types, on PET/MRI-T2 fusion image. Similarly, encasement of adjacent vessels was noted in 43.1 % of solid types and in 6.5 % of cystic types. Particularly in cystic types, intra-tumor structures such as mural nodule (35.4 %) or intra-cystic septum (74.2 %) were detected additionally. Besides, PET/MRI-T2 fusion image could detect extra benign cystic lesions (9.1 % in solid type and 9.7 % in cystic type) that were not noted by PET/CT.In diagnosing pancreatic lesions, FDG-PET/MRI fusion image was useful in differentiating pancreatic cancer from benign lesions. Furthermore, it was helpful in evaluating relationship between lesions and surrounding tissues as well as in detecting extra benign cysts.

Purpose The first aim of this study was to compare the detectability of metastasis of postoperative differentiated thyroid cancer (DTC) among 131I whole body scintigraphy (IWBS), fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT), and diffusion-weighted magnetic resonance imaging (DWI). The second aim was to clarify the association between the image pattern and prognosis.

The deep-inspiration breath-hold PET/CT (DIBH PET/CT) technique improves the limitations of diagnosing a lesion located in an area influenced by respiratory motion that results in spatial misregistrations caused by respiration between PET and CT. However, its reproducibility with regard to calculating the maximal standardized uptake value (SUV(max)) and metabolic volume (MV) in DIBH PET/CT has not been elucidated.The purpose of this study was to investigate the reproducibility of the DIBH PET/CT technique including calculating the SUV(max) and the MV.Sixty patients with various cancers were enrolled. The subjects had 47 abdominal lesions and 28 chest lesions. All patients demonstrated a misregistered image in the early whole-body image taken 50 min after FDG intravenous infusions. We added the delayed spot images 40 min after the first image. On the delayed image, we performed both conventional techniques with non-breath-hold (NBH) and the DIBH technique. In the four times DIBH technique, we obtained the coefficient of variance (CV) in calculating these indices for evaluating reproducibility.The SUV(max) value with DIBH showed an increase of 16.1-60.1% compared with that measured by NBH. The mean value of CV was 5.5 in thoracic lesions and 6.3 in abdominal lesions. The values of MV with DIBH showed a decrease of 14.0-20.1% compared with those measured by NBH. Regarding reproducibility, mean value of CV was 7.1 in thoracic lesions and 11.9 in abdominal lesions.The DIBH technique improves the inaccurate quantification of both SUV(max) and MV. Although the CV value of SUV(max) with DIBH technique is better in thoracic lesions compared with that in abdominal lesions, the reproducibility was acceptable.

The conventional delayed scan in dual phase of thallium-201 ((201)Tl) single-photon emission computed tomography (SPECT) is useful for estimating the viability of non-small-cell lung cancer (NSCLC). However, the influence of tumor blood flow cannot be ignored by the scan at 4 h after the tracer injection. For the purpose of improving the diagnostic capability and for clarifying the association between (201)Tl uptake and proliferative activity, we investigated the usefulness of super-delayed scan obtained at 24 h in triple-phase (201)Tl SPECT.A total of 122 patients with lung nodule, 106 of NSCLC and 16 of benign nodule, were given (201)Tl SPECT before the tumor resection. Early image (15 min), delayed image (4 h), and super-delayed image (24 h) were obtained after intravenous injection of (201)Tl chloride (111 MBq). On the each SPECT image, regions of interest (ROIs) were placed over the tumor contour (T) and contra-lateral normal lung tissue (N) area on one transverse view clearly defined lesions, and T/N ratio on the early image (ER), the delayed image (DR), and the super-delayed image (sDR), and retention indexes (RI and sRI) were calculated. All patients underwent subsequent surgical excision, and the specimens were immunostained for Ki-67 and CD34. The proliferative capability was measured as a percentage of positive nuclear area for Ki-67 (MIB-1 index). The angiogenesis was measured density of positive micro-vessels for CD34 (micro-vessel density, MVD). Correlation analysis was performed to evaluate the relationship between the MIB-1 index, MVD, and SPECT parameters.The diagnostic accuracy of sDR in the differential of NSCLC was higher than that of DR (83.6% vs. 91.8%). Both DR and sDR were positively correlated with MIB-1 index. The correlation coefficient was higher in sDR (0.53 vs. 0.69). The MIB-1 index of the increasing pattern (RIsRI) group was significantly higher (P0.001) than that of the decreasing pattern (RIsRI) group.The super-delayed scan in the triple-phase (201)Tl SPECT is more useful than conventional delayed scan for both the diagnostic capability and assessing proliferation of NSCLC.

Purpose Firstly, to assess the effect of percutaneous endoscopic gastrostomy (PEG) tube placement on gastric emptying, gastrointestinal (GI) tract motility and the rate of gastroesophageal reflux (GER). Secondly, to confirm whether correlations exist between drug absorption behaviour and GI tract motility using the combination method of absorption function analysis with the motility study. Methods Subjects comprised 11 patients with neurological dysphagia. Gastric-emptying scintigraphy was performed both before PEG via nasogastric tube feeding and after PEG placement. After fasting for more than 8 h, each patient was administered 111 MBq of 99mTc-labelled diethylenetriaminepentaacetic acid (DTPA) with a 100 ml liquid meal via a nutrition tube. Dynamic imaging was performed immediately after administration of a radiolabelled liquid meal for a 1 h period and static imaging was performed after 1, 2, 3 and 6 h. Gastric emptying half-time (T50) was calculated in each patient, and GER ratio and GI transit rate were also evaluated. Simultaneously, we administered 10 mg of famotidine in six of the 11 patients and measured serum concentrations of famotidine at 0, 1, 2, 3 and 6 h. Using the time-concentration curve of famotidine, the maximum concentration of famotidine (Cmax) and area under the curve of famotidine (AUCf) were calculated for each patient. Results In seven of 11 patients, T50 changed after PEG placement, but not significantly. The GER ratio was significantly decreased and complicated pneumonia improved after PEG placement. GI transit rate for each GI segment was unchanged after PEG placement. Significant linear correlations were identified between T50 and both Cmax and AUCf. Conclusion Gastric-emptying scintigraphy with Tc-DTPA was effective in the evaluation of GI transit before and after PEG, as well as in assessing GER. Motility and famotidine absorption were maintained after PEG placement. Significant linear correlations were found between T50 and both Cmax and AUCf. These findings suggest that drug absorption may have some relationship between T50. The result may be more reliable with a larger population.

PURPOSE To investigate whether 201Tl uptake is associated with cell proliferation and angiogenesis in non-small-cell lung carcinoma (NSCLC). METHODS Eighty-four patients with scheduled NSCLC underwent 201Tl single photon emission computed tomography (SPECT) imaging: 15 min (early scan) and 240 min (delayed scan) after intravenous injection of 111 MBq of 201Tl chloride. 201Tl indices were calculated on early images (early ratio: ER) and delayed images (delayed ratio: DR). The retention index (RI) was also calculated from these two parameters. Using surgically resected cancer specimens (54 adenocarcinoma, 24 squamous cell carcinoma (SCC), six large-cell carcinoma), immunohistochemical stains for both Ki-67 (MIB-1 index) and CD34 were performed to examine the proliferative activity and the micro-vessel density (MVD), respectively. RESULTS The mean value of 201Tl index was 1.69+/-0.77 (ER) and 2.31+/-1.08 (DR). The average RI was 42.6+/-42.9%, respectively. Both DR and RI positively correlated with MIB-1 index (r = 0.68, P < 0.05 and r = 0.52, P < 0.05). When we analyse adenocarcinoma and SCC separately, there was a significant positive correlation (r = 0.62, P < 0.05) between RI and MIB-1 index in adenocarcinoma but not in SCC (r = 0.20, P = NS). The value of ER positively correlated with MVD (r = 0.75, P < 0.05). It demonstrated strong positive correlation with both histological types (adenocarcinoma: r = 0.80, P < 0.05, SCC: r = 0.66, P < 0.05). CONCLUSION 201Tl SPECT imaging is effective non-invasive method for assessing both the proliferation and the angiogenesis in NSCLC. Both DR and RI are useful indicators for assessing cancer cell proliferation in lung adenocarcinoma. ER is a useful marker for assessing the tumour angiogenesis in NSCLC.

We determined the effect of retention on the changes in regional biodistribution of Tc-99m ECD in the brain. A total of 14 cases, 7 normal volunteers and 7 patients with various diagnoses but with very minimal radiologic findings or none were included in the study. SPECT images were taken at 30 min, 1, 2, 3, 4 and 6 hrs after an intravenous injection. Retention rates were calculated in various regions and were corrected according to the time decay of technetium. There was a tendency for the retention rate to increase up to three hours of imaging and then a decrease was noted in most regions of the brain. In the thalamus, increasing retention was noted. In conclusion, Tc-99m ECD retention in the different regions of the brain varies with time. These differences should always be considered when planning and interpreting SPECT quantitative studies.

Thallium-201 ( 201 Tl) is widely used in the diagnosis of malignant tumours. However, its use in predicting the response to radiation therapy for head and neck cancer has not been established. Nineteen patients with histologically proven head and neck cancer were studied. 201 Tl single photon emission tomographic (SPET) images were obtained 15 min (early) and 4 h (delayed) post-injection of the radionuclide. For a semi-quantitative assessment, regions of interest were drawn over the lesions and normal soft tissue. Lesion-to-normal tissue uptake ratios of 201 Tl activity were measured from mean counts-per-voxel obtained on both the early and delayed scans, representing the early index (EI) and delayed index (DI) respectively. Subsequently, a retention index (RI) was calculated using the formula: RI = (DI - EI) x 100/ (EI). The patients were classified into two groups according to the effect of radiotherapy: a partial response or complete response group (PR-CR group) and a no change group (NC group). In the analysis of primary lesions, both the delayed and retention indexes of the PR-CR group were significantly higher than those of the NC group. However, the early index was not significantly different between the two groups. In the metastatic lymph nodes, only the retention index was significantly different between the two groups. Our results demonstrate that 201 Tl SPET and a 201 Tl index can be used to predict the response to radiotherapy for primary head and neck cancer and lymph node metastases. The retention index is a useful parameter for estimating the effects of radiotherapy.

The relationships of clinical diagnosis, the effect of blood chemistry, and the clinical implication of increased Ga-67 citrate uptake in the bone marrow of patients with signs and symptoms of fever of unknown origin were studied. Based on intensity of Ga-67 citrate uptake in bone marrow, patients were classified as follows: type 1 when there was no evidence or very faint bone marrow uptake in the vertebrae, type 2 when mild to moderate, type 3 when uptake was severe. The relationships of WBC count, hemoglobin, hematocrit, serum iron, and unsaturated iron-binding capacity with the occurrence of increased bone marrow uptake in the different groups were noted. Analysis of variance with Fisher's protected least significant difference was used. A P value of less than 0.05 was considered significant. The results showed significant differences between types 1 and 2 and between types 1 and 3 for WBC counts, hemoglobin, and hematocrit levels. Serum iron concentration and unsaturated iron-binding capacity, however, did not show any significant differences. Significant changes in WBC count, hemoglobin and hematocrit in patients with fever of unknown origin were accompanied by a varying intensity of Ga-67 citrate uptake in the bone marrow.

A 33-year-old, female presenting with dementia was admitted to our institution. Except for slight muscle atrophy noted on both lower extremities there were no other significant physical signs or laboratory findings. Since initial Tc-99m HMPAO SPECT showed hypoperfusion on both temporal, parietal and occipital lobes, follow up study with the same radiotracer was done. Increase in uptake was noted in the left side of the face. There was no abnormality noted on ENT examination. CT scan and MRI showed slight nasal mucosal wall thickening. T1-201 SPECT showed increased uptake in the nasal area. The increase in uptake could be due to nasal mucosal thickening. This could simulate nasal tumor and interfere in determining ROI for brain perfusion studies.

The aim of the study was to evaluate the use of 201 Tl single photon emission tomography (SPET) in differentiating histological types and lymph node sizes of lung tumours based on the early uptake ratio (EUR), delayed uptake ratio (DUR) and retention index (RI). We also wished to compare the effectiveness of 201 Tl SPET and computed tomography (CT) in detecting lymphadenopathy. We examined 41 subjects using both 201 Tl SPET and CT. Fifty-seven lymph nodes were detected and were grouped according to size. The EUR, DUR and RI were determined and analysed using Student's t-test and a P-value 5 cm in size and those 3-5 cm in size, as well as between those 5 cm in size. A significant difference in DUR was seen between lymph nodes 5 cm in size. No significant differences were seen for the RI. The specificity, sensitivity and accuracy of 201 Tl SPET were 81.3, 90.2 and 87.7% respectively, whereas for CT they were 81.3, 100 and 94.74% respectively. In conclusion, quantitative analysis with 201 Tl SPET was unable to differentiate with accuracy between histological types but it could differentiate between nodes of varying sizes. However, CT had a better specificity and accuracy.

Background: Thallium-201 (201Tl) has come to be widely used in the diagnosis of several kinds of malignant tumor, but its usefulness in diagnosing head and neck cancer has not been established. Purpose: This study investigated the usefulness of201Tl SPECT imaging in patients with head and neck cancer histologically confirmed. Methods: Eighteen patients with histologically proven head and neck cancer were studied.201Tl SPECT images were obtained both 15 min and 4 hours after intravenous injection of 148 MBq of201Tl-chloride.201Tl-indices were calculated semiquantitatively to assess the tracer uptake in relation to tumor size and histological type. Results: High201Tl uptake was noted in all primary tumors and metastatic lymph nodes on the both early and delayed images, but201Tl-indices did not show any correlation with tumor size or histological type. Conclusion: Primary head and neck cancer and lymph node metastasis can be effectively visualized with201Tl SPECT. It may provide information in addition to morphological changes and may be a supplemental method to use in the evaluation of head and neck cancer.

To establish the most effective radiation dose for treatment of Graves ophthalmopathy (GO).A combination of 10 Gy (n = 15) or 24 Gy (n = 16) of radiation and corticosteroids was used to treat 31 patients with GO. Magnetic resonance (MR) images obtained before treatment showed swollen extraocular muscles with prolonged T2 relaxation times in all patients.Before therapy, T2 relaxation time of extraocular muscle was 79.6 msec (95% confidence interval, 76.3, 82.9) in the 24-Gy group and 77.4 msec (95% confidence interval, 74.6, 80.1) in the 10-Gy group (P = .32). After therapy, T2 relaxation time was 62.8 msec (95% confidence interval, 61.2, 64.4) in the 24-Gy group and 68.9 msec (95% confidence interval, 66.8, 71.1) in the 10-Gy group. In the 24-Gy group, there was a significant decrease in T2 relaxation times (P = .001) and clinical response to initial treatment was better. At 1- and 3-month follow-up, the resistance rate was lower in the 24-Gy group.In treatment of GO, 24 Gy of radiation is a more effective dose than 10 Gy when combined with systemic corticosteroids.

The aims of this study were (1) to compare N-isopropyl-p-[I-123]-iodoamphetamine (123I-IMP) SPET with computed tomography (CT) in chronic-stage head trauma patients with neurological abnormalities and (2) to quantify regional cerebral blood flow (rCBF) in patients with chronic-stage head trauma. 123I-IMP SPET and CT were performed in 23 patients with chronic-stage head trauma and 12 normal controls. Both types of imaging were evaluated visually. In addition for the SPET images, the rCBF in 12 regions (bilateral frontal cortex, temporal cortex, parietal cortex, occipital cortex, perilolandic area, cerebellum: total 276 regions) was analysed quantitatively using a reference sampling method. In total, 39 focal lesions related to neurological abnormalities were detected. Although 22 (56.4%) lesions were observed using both CT and SPET, another 17 (43.6%) were detected by SPET only. The mean rCBF in the localized lesions of each lobe, which correspond to low-density areas (LDAs), were lower on CT than those of each lobe seen only on SPET. These rCBF values were lower than the mean rCBF values in the lobes of the controls. The mean rCBF values in each lobe with visually normal tracer uptakes were also significantly lower in the 23 patients than in the controls. 123I-IMP SPET is useful for demonstrating brain dysfunction in morphologically intact brain regions and for providing objective evidence to account for the clinical presentation of patients presenting with chronic traumatic brain injury.

Tl-201 SPECT and Tc-99m-Human serum albumin (HSA) multigated radionuclide ventriculography were performed on 11 patients with progressive muscular dystrophy (Becker type 2, Fukuyama type 2, Limb-girdle type 7) to evaluate myocardial involvement. Hypoperfusion was detected in 8 patients on Tl-201 SPECT. Decreases in both systolic function (left ventricular ejection fraction; LVEF) and diastolic function (peak filling rate; PFR) were also seen in these patients. A high incidence of myocardial involvement of these kinds of progressive muscular dystrophy was suggested.

Sympathetic stimulation of the Muller muscle may be responsible for most of the medically reversible cases of eyelid retraction in patients with Graves disease. The authors studied 21 patients with class I Graves ophthalmopathy (GO), 32 patients with Graves disease without ophthalmopathy (GD), and 12 control subjects. T1-weighted spin-echo magnetic resonance (MR) imaging was performed with a 0.5-T superconducting system. The thickness of the levator palpebrae superioris muscle was determined from sagittal MR images. The thickness of the levator muscles in patients with GD did not differ from the thickness in control subjects, but the levator muscles in patients with GO were significantly thickened (P < .01). The thickness of the levator muscles in patients with GO was significantly greater than in those of patients with GD (P < .01). In 64 orbits of patients with GD, 3% of levator muscles were thickened. In 33 of 40 (83%) orbits of patients with GO presenting with upper eyelid retraction, the levator muscles were thickened. Sagittal MR imaging demonstrated thickening of the levator muscles in patients with persistent upper eyelid retraction. The authors conclude that a thickened levator muscle probably causes upper eyelid retraction in patients with GO.

Predicting liver functional reserve is important before partial hepatectomy. However, it is difficult to predict using morphologic imaging modalities, such as CT and MRI. In this study, we assess the usefulness of galactosyl human serum albumin (GSA) scintigraphy in predicting liver function recovery. We performed 99mTc-GSA scintigraphy before operation in 56 patients. Each patient was administered 185 MBq of 99mTc-GSA by intravenous injection. Serial images were taken immediately after the administration for 40 min. SPECT images were obtained to make a functional map. We calculated the functioning parameter residual GSA-Rmax (GSA-RL) using analysis software developed by Dr. N. Shuke. In addition, we compared GSA-RL with the morphological parameter residual liver volume (RLV-CT) calculated by conventional CT and serum albumin (Alb) or cholinesterase (ChE). We analyzed the correlation between imaging parameters and the postoperative recovery periods of serum albumin (r-Alb) and cholinesterase (r-ChE) and the values at 1 and 3 months for serum albumin (1M-Alb, 3M-Alb) and cholinesterase (1M-ChE, 3M-ChE). We found significant correlations between GSA-RL and r-Alb, r-ChE, 1M-Alb, 3M-Alb, 1M-ChE and 3M-ChE, but not between RLV-CT and the same parameters. The GSA-RL calculated by 99mTc GSA-SPECT was a useful parameter for predicting postoperative liver function recovery that should be implemented before partial hepatectomy.

The authors performed both Tc-99m HMPAO and Tl-201 scintigraphy in 30 patients with thyroid tumors (21 papillary adenocarcinoma, three solid follicular adenoma, six adenomatous goiter with cystic degeneration). Increased accumulation of both Tc-99m HMPAO and Tl-201 was seen in 14 patients with papillary adenocarcinoma and three with solid follicular adenoma, whereas two patients with papillar adenocarcinoma had low accumulation of both tracers. Of the six patients with adenomatous goiter with cystic degeneration, four had low accumulation of both Tc-99m HMPAO and Tl-201, and one patient had low accumulation of Tc-99m HMPAO only. Iso accumulation (same accumulation as the normal thyroid) of Tc-99m HMPAO was seen in five patients with papillary adenocarcinoma and one with adenomatous goiter. The distribution of Tc-99m HMPAO in the thyroid tumors and normal thyroid tissue was independent of time from 2 to 120 minutes after injection. The results of dynamic studies using Tc-99m HMPAO suggested that the accumulation of Tc-99m HMPAO in thyroid tumors reflected mainly tumor blood flow. The resultant Tc-99m HMPAO images were essentially similar to the Tl-201 images obtained 10 minutes after injection. Tc-99m HMPAO imaging can be a suitable substitute for Tl-201 imaging, and it may possibly be used to estimate tumor blood flow in patients with thyroid tumors.

BACKGROUND The deep-inspiration breath-hold F-fluorodeoxyglucose PET/computed tomography (DIBH F-FDG PET/CT) technique improves the limitations of diagnosing a lesion located in an area influenced by respiratory motion that brings about spatial misregistration caused by respiration between PET and CT. However, its clinical effectiveness with regard to abdominal lesions has not been elucidated. The influence of respiratory motion for calculating the maximal standardized uptake value (SUVmax) and metabolic volume (MV) in DIBH F-FDG PET/CT has not been investigated either. OBJECTIVE The purpose of this study was to investigate the usefulness of the DIBH F-FDG PET/CT technique in diagnosing liver tumors, bile duct cancers, and pancreas tumors. In addition, we compared the values of SUVmax and MV between DIBH and nonbreath-hold (NBH). METHODS Forty patients with various abdominal malignancies including liver tumors, bile duct cancers, and pancreas tumors were enrolled. In total, the patients had 47 abdominal lesions. All patients showed a misregistered image in the early whole-body image taken 50 min after intravenous F-FDG infusions. We added the delayed images 40 min after the first image. On the delayed image, we carried out both conventional techniques with normal respiration (NBH) and the DIBH technique. Finally, we compared two kinds of images in each patient. At the same time, we compared both SUVmax and MV of cancer obtained by the two kinds of imaging methods. RESULTS In 14 lesions (29.8%), we corrected the anatomical tumor location, from the incorrect to the correct organ, by the DIBH technique. In 22 lesions (46.8%), we corrected the tumor location within the organ. Consequently, tumor staging also changed in 11 patients (23.4%) after correction by the DIBH technique. Regarding the SUVmax value by DIBH, it showed an increase of approximately 15.0-58.6% compared with that measured by NBH. In contrast, the value of MV by DIBH showed a decrease of 20% compared with that measured by NBH. CONCLUSION The DIBH F-FDG PET/CT technique is feasible for accurate localization when diagnosing of liver tumors, bile duct cancers, and pancreas cancers. The DIBH technique also improves the inaccurate quantification of both SUVmax and MV.

(123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a useful tool for differentiating idiopathic Parkinson's disease (PD) from parkinsonism (PS) caused by other disorders. However, cardiac MIBG uptake is affected by various causes. Alternatively, hypoperfusion in the occipital lobe of PD is reported recently.The objective is to clarify the correlation between regional cerebral blood flow (rCBF) alteration and cardiac MIBG uptake in PD. In addition, we examined whether additional brain perfusion analysis improved the differential diagnostic ability for PD from PS when compared with MIBG scintigraphy alone.Forty-nine patients with PD (27 mild groups: Hoehn and Yahr stages I, II; 22 severe groups: Hoehn and Yahr stages III, IV) and 28 patients with PS participated. We compared absolute rCBF values between PD and PS. In addition, we determined correlation between MIBG parameters and each rCBF value. Finally, we compared the diagnostic ability for the differentiation of PD from PS between two diagnostic criteria, each MIBG index abnormality alone [heart-to-mediastinum ratio, H/M (E)1.9, H/E (D)1.7, washout rate40%] and each MIBG index abnormality or occipital lobe hypoperfusion (36 ml/100 g per min).Absolute rCBF value of occipital lobe was significantly lower in severe PD as compared with PS or mild PD. In the correlation analysis, rCBF of occipital lobe correlated positively with MIBG parameters (H/M). Regarding the diagnostic ability, sensitivity improved by accounting for occipital hypoperfusion as compared with MIBG indices alone. In contrast, neither specificity nor accuracy improved by adding occipital lobe analysis.MIBG parameters (H/M) correlated positively with occipital hypoperfusion in PD. In the differential diagnosis between PD and PS, although its usefulness might be limited, analysis of rCBF in the occipital lobe added to (123)I-MIBG myocardial imaging can be recommended.

The objective of the present study is to investigate the correlations across various types of interface software for 201Tl gated myocardial perfusion SPECT (MPS) in calculating two common diastolic function parameters (DFx), peak-filling rates (PFR), and time-to-peak filling (TTPF). A total of 109 patients (66 men and 43 women; age 35–78 years) were studied. All patients were classi-fied into three groups (i.e., ND, no-defect group; SD, small-defect group; LD, large-defect group) to clarify the influence of perfusion defects possibly affecting the analysis. Two kinds of available software, namely, quantitative gated SPECT (QGS2) and perfusion and functional analysis for gated SPECT (pFAST2) with cardioGRAF were used to obtain PFR and TTPF. Finally, we analyzed the correlation between DFx obtained with the two different kinds of software. The values of LVEF, PFR, and TTPF were assessed in all patients. In both the ND (correlation coefficients were 0.92, 0.79, and 0.99, respectively) and SD groups (correlation coefficients were 0.74, 0.88, and 0.98, respectively), a strong correlation was observed. In contrast, PFR did not show a significant correlation in the LD group. With the two different kinds of software, QGS2 and pFAST2, the calculated PFR was almost equal and showed good correlations in both ND and SD groups. In contrast, the numerical value varied between the two methods, and its correlation was poor in the LD group. However, TTPF showed a good correlation regardless of the presence of perfusion defects, and the values were equal. TTPF was confirmed to be a stable diastolic index across the two kinds of software, QGS2 and pFAST2, in 201Tl gated MPS.

Chronic pain is defined as intractable pain caused by abnormal pain transmission or impairment of the pain control system per se. Alteration of regional cerebral blood flow (rCBF) is known to occur under the presence of pain stimulation. Epidural spinal cord stimulation (SCS) is occasionally effective in relieving the symptom. The aim of the current study is to investigate the alteration of rCBF in baseline condition and to find the association between the rCBF change and the efficacy of SCS in chronic pain. A total of 18 patients underwent Tc-99m-HMPAO SPECT before and after SCS. Analysis with three-dimensional stereo-tactic surface projections (3D-SSP) with stereo-tactic extraction estimation (SEE) software was adopted to evaluate the rCBF. We assessed the extent score of the abnormal region in each segment (rate of the coordinates with a Z-value that exceeds three kinds of threshold value 2.0, 2.5 and 3.0 in all coordinates within a segment). According to the therapeutic response defined by visual analogue scale, we categorized patients into two groups, the good responder (GR) group (n = 12) and poor responder (PR) group (n = 6). In the analysis, we compared the extent score in the following two conditions. (1)Comparison between the PR group and normal control group under both baseline condition and after SCS. (2)Comparison between the GR group and normal control group under both baseline condition and after SCS. (1)In the PR group, increased rCBF was observed in left thalamus, bilateral precuneus and bilateral cerebellum under the baseline condition. After SCS, the range of these increased rCBF areas localized but remained. Decrease of rCBF was noted in bilateral subcallosal gyrus, superior temporal gyrus (STG) and bilateral anterior cingulate gyrus (ACG). They localized after SCS, but remained. (2)In the GR group, increased rCBF areas were noted in bilateral precuneus and bilateral cerebellum under the baseline condition. After SCS, they localized in bilateral precuneus but those of bilateral cerebellum remained. Decreased rCBF area was noted in bilateral subcallosal gyrus, STG and bilateral ACG under the baseline. After SCS, they localized in bilateral subcallosal gyrus and bilateral STG. In contrast, they enlarged in bilateral ACG. Chronic pain patients demonstrated abnormal rCBF distribution on both baseline and post SCS conditions. Increased rCBF of thalamus and precuneus under both conditions in the PR group and decreased rCBF of ACG under post SCS conditions in the GR group were characteristic patterns. Tc-99m-HMPAO SPECT with 3D-SSP and SEE analysis is likely objective and effective in monitoring and evaluating therapeutic outcome by SCS in chronic pain. In addition, it provides information that is useful in the selection of SCS candidates.

123 I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a useful tool for diagnosing cardiac autonomic neuropathy (CAN) in non-insulin-dependent diabetes mellitus (NIDDM). However, the long-term prognostic value for cardiac events or mortality in NIDDM has not been clarified. We investigated the long-term prognostic value of cardiac MIBG imaging for both cardiac event and mortality owing to a variety of causes of death in NIDDM. 144 NIDDM patients were analyzed retrospectively with the end-points of a cardiac event and various causes of mortality. The heart-to-mediastinum uptake ratio on the delayed image (H/M [d]) was obtained from anterior planar imaging. The mean follow-up period was 7.2 ± 3.2 years. Seventeen patients had a cardiac event onset and 7 patients died during observation. During the same observation course, 16 patients died, including some who died of cardiac event. Both multivariate and univariate analyses revealed that decreased H/M (d) (< 1.7) was the independent predictor of long-term mortality for a variety of causes of death. Although the value of H/M (d) was not a significant prognostic factor for predicting a cardiac event, CAN, diagnosed by a combination of H/M (d) and coefficient variance of RR interval, was an independent predictor for the cardiac event in NIDDM. MIBG myocardial scintigraphy was useful for predicting cardiac events and long-term mortality in NIDDM.

The current study is an investigation of alterations in regional cerebral blood flow (rCBF) distribution in patients with transient hypothyroidism after thyroidectomy. In addition, the effects of thyroxine treatment on rCBF changes were studied. Noninvasive rCBF measurements using99mTc-HMPAO SPECT were performed on 24 post-thyroidectomy patients who were in a hypothyroidic state. The measurements were conducted before131I therapy and after thyroid hormone (thyroxine) replacement. We used adjusted rCBF images (normalization of global CBF for each subject to 50 m//100 g/min with proportional scaling) to compare these data with age-matched normal control groups (n=15) using SPM96. We also compared the absolute rCBF value of hypothyroidic patients with those of normal control groups. In addition, the association between rCBF alteration and the severity of depression was also analyzed. Finally, the effect of thyroid hormone replacement on rCBF was investigated individually using the Jack-knife test, in which patient data were compared with those from healthy volunteers. According to the result of this test, all cases were categorized into three subgroups, namely, improved, unchanged group and normal. To prove the reversibility of rCBF alteration after thyroid hormone replacement, a group comparison test between the normal controls and the improved group was done before and after thyroid hormone replacement. Similarly a group comparison test between the unchanged group and normal controls was also performed. In the hypothyroidic condition, there was a significant decrease in the posterior part of the bilateral parietal lobes and in part of the bilateral occipital lobes, including the cuneus. These decreased rCBF areas extended to the bilateral prefrontal cortices as deterioration became more profound. On individual analysis, 16 of 24 patients (66.7%) demonstrated rCBF reduction, while 8 patient did not show significant rCBF change (33.3%, the normal group). After thyroxine replacement, improvement of rCBF was noted in nine of 16 patients (56.3%, the improved group). In seven of 16 patients (43.7% the unchanged group), the significant low rCBF area remained unchanged. Compared with the normal controls, the improved group showed significantly decreased rCBF of the bilateral parietal lobe and the occipital lobe in the hypothyroic condition. After thyroid hormone replacement, these abnormal rCBF areas disappeared. In contrast, in the unchanged group, the significant hypoperfusion area became localized but remained. 99mTc-HMPAO SPECT and SPM96 analysis demonstrated a significant rCBF decrease in the parietal lobe and part of the occipital lobe in patients with induced transient hypothyroidism after thyroidectomy. This phenomenon might contribute to understanding of the depressive state. Recovery of rCBF after thyroid hormone replacement was confirmed in some patients. However, rCBF improvement did not always occur in every patient during the follow up period. The reversibility of rCBF in transient hypothyroidism may be dependent on individual characteristics during a short-term period.

We performed123I-MIBG (MIBG) myocardial scintigraphy twice in patients with noninsulin-dependent diabetes mellitus (NIDDM) to investigate whether MIBG distribution was improved by pertinent clinical control. To determine the influential factors for MIBG distribution, we investigated the association between various clinical parameters and the serial change in MIBG uptake parameters.Patients and Methods: Twenty NIDDM patients with no cardiac disorders were evaluated. Planar images were taken at 30 minutes (early) and 3 hours (delayed) after MIBG injection. The heart-to-upper-mediastinum uptake ratio (H/M) and washout ratio (WR) were calculated as parameters for estimating cardiac sympathetic function. Patients were divided into two groups, eight in the improved group and twelve in the unimproved group, according to the serial change in H/M. The mean interval between the baseline and the follow up study was 2.1±0.6 year. Differences between the means of the laboratory data in patients in both groups were compared for the baseline and the follow up study by using the paired t-test. As a means of determining the influential factors for a serial change of MIBG uptake, Fisher’s exact test was performed to evaluate the association between the serial change in cardiac MIBG parameters and changes in other clinical parameters, such as blood sugar (BS) control, BS control method (insulin therapy), serum cholesterol control, and severity of diabetic complications. We also analyzed the association between the changes in CVR-R (coefficient variance of R-R intervals at rest ECG) or NCV (velocity of posterior tibial nerve) and those of other clinical parameters. Associations among these neurological parameters (MIBG parameters, CVR-R and NCV) were also analyzed.Results: Paired t-tests showed a significant decrease in fasting blood sugar and fructosamine in the improved group in the follow up study compared to those in the baseline study. Nevertheless, Fisher’s exact test showed no significant association between FBS, HbA1C, fructosamine and the improvement in cardiac MIBG uptake. The only significant association was observed between the serial change in H/M and the BS-control method (insulin therapy). Within the neurological parameters, a significant association was noted between the serial changes in H/M and CVR-R.Conclusion: Although BS control was likely to be an important factor, it did not always ameliorate cardiac MIBG uptake. Based on the significant association between the BS-control method (insulin therapy) and MIBG uptake change, the severity of diabetes mellitus was likely to be a more influential factor. It was suggested that cardiac MIBG uptake could improve within the mild stage if controlled by diet therapy or an oral hypoglycemic agent in NIDDM.

The aim of this study was to evaluate the efficacy and role of technetium-99m tetrofosmin for the detection of abnormal parathyroid glands to be referred for surgical treatment. Twenty-eight consecutive patients, including 25 primary and 3 secondary cases of hyperparathyroidism, were evaluated. (99m)Tc-tetrofosmin/(99m)Tc-pertechnetate subtraction scintigraphy (TF/Tc) was performed on all patients, and the results were directly compared with those of (99m)Tc-methoxyisobutylisonitrile (MIBI)/(99m)Tc-pertechnetate subtraction scintigraphy (MIBI/Tc), (201)Tl/(99m)Tc-pertechnetate subtraction scintigraphy (Tl/Tc), magnetic resonance imaging (MRI) and ultrasonography (US). In cases of single-gland disease, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 63.2%, 68.4%, 57.9%, 55.6% and 63.2%, respectively. In cases of multi-gland disease, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 41.7%, 41.7%, 37.5%, 58.3% and 54.2%, respectively. In cases of parathyroid adenoma, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 68.8%, 75.0%, 68.8%, 62.5% and 75.0%, respectively. In cases of parathyroid hyperplasia, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 40.7%, 40.7%, 33.3%, 53.8% and 48.1%, respectively. It is concluded that, for the detection of abnormal parathyroid glands, (99m)Tc-tetrofosmin is as useful as (99m)Tc-MIBI and is more useful than (201)Tl.

PURPOSE: To evaluate the CAD system for screening mammograms. MATERIALS AND METHODS: Mammograms of patients with asymptomatic breast cancerwere examined retrospectively. A total of 260 screening mammograms from 65 patients (bilateral cranio-caudal and medio-lateral-oblique views from each) were tested by using the CAD system (ImageChecker M1000 system, R2 Technology, Los Altos, CA, USA). Results: With 0.58 microcalcifications marks/film and 0.20 mass marks/film set as the false positive rate, 100% of microcalcifications cases and 79% of mass cases were detected correctly. Conclusion: The CAD system has the potential to become a second reader. Further developments are expected to improve the accuracy of detection of mass lesions

A total of 24 patients with a mean age of 45.8 +/- 20.8 were included in the study. The patients were grouped as Control (C), Degenerative Syndromes (DS), Degeneration Associated with External Factors (DEF), Degeneration Associated with Focal Neurologic Lesion (DFN) and Demyelinating Disease (DM). Imaging started 15 minutes for early and 4 hours for delayed scans after i.v. infusion of I-123 IMP. The rCBF was calculated by the IMP autoradiographic (ARG) method. The wash-out ratio (WR) was calculated as the ratio of the Delay/Early count. In the rCBF of the various areas of the brain, significant differences were noted between various disease groups. No correlation was noted between rCBF and WR (r = -0.50). The WR of patients grouped according to various disease processes did not show a significant difference between various areas of the brain. In conclusion, the rCBF was effective in separating both various areas of the brain and disease entities. WR from a delayed study is less useful in neurodegenerative diseases.

To investigate the influence of diabetic myocardial damage (suspected myocardial damage; SMD) diagnosed by 201Tl-SPECT and diabetic cardiac autonomic neuropathy (AN) on myocardial MIBG uptake in patients with non-insulin-dependent diabetes mellitus (NIDDM).Eighty-seven diabetic patients divided into four subgroups: 23 with SMD (+) AN (+); 19 with SMD (+) AN (-); 27 with SMD (-) AN (+); 18 with SMD (-) AN (-), and 10 controls were studied. Both planar and SPECT images were taken at 30 minutes (early) and 3 hours (delayed) after 123I-MIBG injection. The heart to mediastinum uptake ratio (H/M) and washout ratio of 123I-MIBG (WR) were obtained from both planar images. On SPECT images, the total uptake score (TUS) was obtained by the 5 point score method by dividing the myocardium into 20 segments on visual analysis. Similarly, the difference between the 201Tl image and the 123I-MIBG image in TUS was taken as the difference in the total uptake score (delta TUS) representing cardiac sympathetic denervation without SMD.On both early and delayed planar images, the mean H/M value in the subgroups of diabetic patients was significantly lower in the SMD (+) AN (+) group than in the control group, but among those subgroups, there was statistically significant difference between the SMD (+) AN (+) and SMD (-) AN (-) groups only on the delayed images. Regarding the WR value, there was no statistically significant difference among subjects. On SPECT image analysis, the diabetic subgroup with AN or SMD had statistically significant lower values for TUS than those of the control group. Among diabetics, there was a statistically significant differences between SMD [+] AN [+] and SMD [-] AN [-] on both early and delayed images. Similarly, the SMD [+] AN [-] group also had significantly lower values than those of SMD [-] AN [-] on early images. Regarding delta TUS, there was a statistically significant differences between AN [+] subgroups and controls. Similarly, the mean value for delta TUS was much higher in AN [+] subgroups than in AN [-] subgroups with or without SMD in diabetes mellitus.123I-MIBG myocardial uptake is affected by both SMD and cardiac autonomic neuropathy. Based on the finding that delta TUS was much higher in AN [+] subgroups and there was no statistically significant difference between SMD [+] AN [+] and SMD [-] AN [+] subgroups, a decrease in myocardial 123I-MIBG uptake might progress independently of SMD.

We assessed the relationship between 99Tcm-HMDP extraosseous accumulation (EOA), the histopathology of primary lesions and various laboratory findings. In 155 of 4824 patients, 163 EOA were noted. Of these, 33.7% were in the abdomen, 27.6% in the chest, 22.7% in the extremities, 9.8% in the pelvic area and 6.1% in the head and neck area. We found that 72.4% of EOA were due to malignant processes and 27.6% to benign processes. In the abdomen, 36.6% of the EOA were due to hepatocellular carcinoma and intestinal carcinoma. In the chest, 46.7% of EOA were a result of breast carcinoma. In the extremities, 28.7% of the EOA were due to sarcoma. The mean white blood cell count was elevated (8.0 +/- 6.3 x 10(3)) in patients with malignant processes. The mean serum haemoglobin and haematocrit in benign and malignant processes, for both males and females, were below normal values. All other laboratory findings were within normal limits. Significant differences in serum haemoglobin and haematocrit were noted between male and female patients with benign processes (P = 0.04 and P = 0.04, respectively). No other significant differences between benign and malignant processes were noted. Therefore, EOA is more frequently associated with malignant processes of primary lesions and is often accompanied by leukocytosis and anaemia.

To evaluate spin-echo and contrast material-enhanced dynamic magnetic resonance (MR) imaging in characterization of thyroid and parathyroid masses.Conventional T1- and T2-weighted, gadolinium-enhanced dynamic, and gadolinium-enhanced T1-weighted spin-echo imaging sequences were performed in 85 patients with thyroid and parathyroid tumors. Findings from spin-echo imaging and dynamic curve patterns from mean signal intensity ratios were evaluated for each histologic tumor type.T1- and T2-weighted imaging did not enable differentiation of benign from malignant tumors. Primary thyroid lymphoma enhanced less than other solid thyroid tumors, and parathyroid adenoma also enhanced less than other tumors (P.05 compared with papillary carcinoma.Gadolinium-enhanced MR imaging cannot enable prediction of histologic type in thyroid and parathyroid tumors. However, in cases of multiple tumors, the technique may improve the contrast between the different histologic types and sometimes suggest the diagnosis of primary thyroid lymphoma or parathyroid adenoma.

Summary The aim of this study was to investigate the relationship between autonomic nerve dysfunction and myocardial uptake of l23I-meta-iodobenzyl guanidine (MIBG) in patients with diabetes mellitus. Twenty-two non-insulin-dependent diabetic patients, 9 with autonomic neuropathy [ANP( + )] and 13 without autonomic neuropathy [ANP( -)], and 8 controls were included in the study. Both planar and single photon emission tomographic (SPET) images were obtained 30 min (early) and 3 h (delayed) after the 123I-MIBG injection. The heart-to-mediastinal uptake ratio (H/M) and the washout ratio of 123I-MIBG (%WR) were calculated from planar images. The uptake ratio of the inferior wall to the anterior wall (I/A) and the %WR of both the inferior and anterior walls were calculated from the SPET images. On the early planar images, the mean H/M ratio in the ANP( + ) group was significantly lower than that of the control group. The mean %WR on the planar images in the ANP( - ) group was significantly higher than that of the controls. The SPET images demonstrated a reduction in MIBG uptake and significantly increased clearance in the inferior wall of the ANP( - ) patients. These findings extended to other areas of the heart in the ANP( + ) patients. In the quantitative analysis of the SPET images, the ANP( + ) group had significantly lower I/A values and significantly higher %WR values in the anterior wall. The ANP( + ) group showed significantly increased clearance of 123I-MIBG in the inferior wall. We conclude that 123I-MIBG myocardial scintigraphy is a useful diagnostic tool both in the early detection and evaluation of the progression of myocardial sympathetic nerve dysfunction in patients with diabetes mellitus. Both the I/A and %WR calculated from SPET images are useful parameters.

To determine if T2 relaxation time measurements with magnetic resonance (MR) imaging in patients with Graves ophthalmopathy (GO) can predict response to therapy.Studied were 84 patients with GO, 27 with Graves disease without ophthalmopathy (GD), and 12 control subjects without Graves disease. T2 times of extraocular muscles and retrobulbar fat tissue were measured. Twenty-five patients with GO were treated with systemic corticosteroids and retroorbital radiation therapy.T2 relaxation times of muscles in patients with GD were the same as those in controls but were longer in patients with GO (P.05). T2 times of fat in all patients were the same as those of the controls. The predicted probability of response to treatment increased with increased mean T2 relaxation times of extraocular muscles prior to therapy. Of the 25 patients with combined therapy, only those with particularly prolonged T2 relaxation times showed impressive response.T2 relaxation time measurements with MR allow noninvasive detection of acute muscle inflammation and predict which patients with GO will likely benefit from antiinflammatory therapy.

Time sequential single photon emission computed tomography (SPECT) studies using thallium-201 were performed in 25 patients with brain tumours to evaluate the kinetics of thallium in the tumour and the biological malignancy grade preoperatively. After acquisition and reconstruction of SPECT data from 1 min post injection to 48 h (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 15-20 min, followed by 4-6, 24 and 48 h), the thallium uptake ratio in the tumour versus the homologous contralateral area of the brain was calculated and compared with findings of X-ray CT, magnetic resonance imaging, cerebral angiography and histological investigations. Early uptake of thallium in tumours was related to tumour vascularity and the disruption of the blood-brain barrier. High and rapid uptake and slow reduction of thallium indicated a hypervascular malignant tumour; however, high and rapid uptake but rapid reduction of thallium indicated a hypervascular benign tumour, such as meningioma. Hypovascular and benign tumours tended to show low uptake and slow reduction of thallium. Long-lasting retention or uptake of thallium indicates tumour malignancy.

Myocardial dysfunction in 14 patients with Duchenne's muscular dystrophy (DMD) was evaluated by Tc-99m HSA multigated radionuclide ventriculography (MGRV). Follow-up studies were performed on eight patients for 5 years. Left ventricular ejection fraction and standard deviation of the phase angle were abnormal in all patients older than 15 years. Hypokinetic changes and phase delay were recognizable in most patients older than 17 years. Peak filling rate decreased in patients older than 17 years. MGRV was considered an effective method for evaluating serial changes in cardiomyopathy of patients with DMD.

Cerebral blood flow imaging with N-isopropyl (I-123) p-iodoamphetamine (IMP) was performed in 44 patients with ischemic cerebrovascular disease (CVD) at an acute or subacute stage less than 30 days from the onset. IMP imaging was obtained at 20 minutes (early scan) and 4 hours (delayed scan) after intravenous injection of 222 MBq of IMP. The region of interest (ROI) was selected in a slice compatible with the findings on the CT images, and the lesion to tissue ratio (L/T ratio) was calculated in a comparison with the unaffected side. The redistribution index (RI) was also calculated by dividing the difference between the L/T ratio in early and delayed image by the L/T ratio in the early image. The patients were classified into three groups (Grade 1, 2, 3) on the basis of the CT findings. The L/T ratio in the delayed images and RI was high in grade 1 and 2 groups and low in grade 3 groups both in early and delayed scans. The RI had tendency to grow high as the days after the onset became later. In the duration period from 4 to 7 days, 'reversed' redistribution was observed in 4 cases. Follow up examinations were performed in 6 cases in grade 3 group. The RI became higher in 3 cases and lower in 3 cases in the second examination. In conclusion, good redistribution was observed in grade 1 and 2 groups, and the prognosis was good. On the other hand, poor redistribution was observed in grade 3 group.(ABSTRACT TRUNCATED AT 250 WORDS)

In a 43-year-old woman with fibrous dysplasia of the ribs and facial bone and in a 40-year-old man with fibrous dysplasia of the facial bone, there were considerable increases in the uptake of Tc-99m methylenediphosphonate (Tc-99m MDP) and Gallium-67 citrate. Fibrous dysplasia should be added to differential diagnosis of high Gallium-67 citrate uptake in the bone lesions.

A 32-year-old man had a giant pigmented nevus in general at birth in the head, face, chest, and back, and mental retardation and right hemiparesls (unknown cause) developed. A malignant melanoma was suspected on clinical evidence plus the images. At cranlotomy, an intracranial primary malignant melanoma was diagnosed that originated in the pia matter with neurocutaneous melanosis.

Regional cerebral blood flow (rCBF) was measured using N-isopropyl-123I-iodoamphetamine (123I-IMP) with single photon emission computed tomography (SPECT) in 27 patients with diabetes mellitus with an average age of 64.1 years and with an average fasting plasma glucose of 145 mg dl-1. Their data were compared with those of 12 non-diabetic subjects with an average age of 64.6 years. None had cerebral infarction on computed tomographic (CT) studies. There were no significant differences in the physiological or laboratory data between the diabetic and non-diabetic groups except for their fasting plasma glucose and HbA1c levels. A reference sampling method using continuous arterial blood sampling was employed to quantify the rCBF. The average rCBF in each region of the cerebrum and cerebellum was significantly lower in the diabetic group than in the non-diabetic group (P < 0.01). Although a definite cause was obscure, the rCBF of the diabetic patients was reduced even in the absence of findings indicative of cerebral infarction on a CT study.