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A 76-year-old man with symptomatic bone metastases from castration-resistant prostate cancer underwent Radium-223-dichloride (Ra-223) therapy. Before Ra-223 therapy, he had normal peripheral blood cell counts. Ra-223 therapy relieved his shoulder and low back pain. The elevation of the serum prostate-specific antigen (PSA), doubling every month during Ra-223 therapy, suggested a PSA flare or relapse. Some lesions showed decrease and some lesions showed increase on Tc-99m hydroxymethylene diphosphonate bone scintigraphy at two weeks after the third injection of Ra-223 therapy. Ra-223 therapy was discontinued due to thrombocytopenia that was getting worse rapidly. After treatment discontinuation, namely four weeks after the third injection of Ra-223, F-18 fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/CT and a biopsy were performed to evaluate for metastases, and bone marrow metastases were found. Ra-223 was effective for osteoblastic lesions, but not for bone marrow metastases. FDG PET/CT, but not a Tc-99m based bone scan, detected diffuse bone marrow involvement by cancer. This case report is the first to clarify the utility of FDG PET for the detection of bone marrow metastases confirmed by pathological examination in Ra-223 therapy for progressive castration-resistant prostate cancer.

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(Background) Long-term care is necessary for normal growth and development of pediatric recipients of kidney transplants. We report on our experience with pediatric kidney transplantation (KTx) during the past 19 years. (Methods) We retrospectively analyzed the data from 26 recipients who received KTx between 1996 and 2014 at Niigata University Hospital (one patient underwent two consecutive KTx during the designated period). All recipients were 16 years old or younger at the time of KTx. (Results) The graft survival rates at 1, 5, and 10 years after transplantation were 96%, 96%, and 88%, respectively. Three recipients lost the renal graft function due to graft thrombosis, antibody mediated rejection and steroid resistant rejection. Drug non-adherence was associated with rejection episodes, which led to the increasing of estimated glomerular filtration rate (eGFR) level. In addition, renal graft function was related to the growth after KTx. Eighteen recipients graduated from high school during follow-up periods and 17 recipients obtained employment. (Conclusion) Interventions promoting adherence should be implemented among pediatric recipients and parents to optimize graft survival and growth after KTx. Successful KTx contributed the high rate of social participation and employment after pediatric KTx.

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PURPOSE: To investigate the diagnostic and prognostic value of (18)F-FDG-PET/CT for axillary lymph node (LN) staging in breast cancer patients, employing histologic evaluation as the reference. METHODS: Among 196 patients with biopsy-proven breast cancer who had undergone (18)F-FDG-PET/CT before mastectomy or breast-conserving surgery with sentinel LN biopsy and/or axillary LN dissection, 200 axillae were retrospectively analyzed by visual assessment and quantitatively using SUVmax. LN SUVmax as well as other clinicopathological features were assessed for their prognostic value using the log-rank test and Cox method. RESULTS: Metastasis was diagnosed histopathologically in 56 (28 %) axillae. The sensitivity, specificity, and accuracy of visual PET/CT for diagnosing node metastasis were 55.4, 95.8, and 84.5 %, respectively. When the optimal discriminative SUVmax cutoff was 1.5, these figures were 51.8, 97.2, and 84.5 %, respectively. Fourteen of 55 patients (25.5 %) with LN metastases suffered a recurrence during follow-up (median 39 months). Patients with a high nodal SUVmax (≥1.7) had a significantly lower progression-free survival rate than those with a low SUVmax (p = 0.0499). Axillary nodal and primary tumor SUVmax as well as estrogen receptor status were significantly associated with recurrence. CONCLUSION: Axillary nodal SUVmax may be a prognostic indicator of disease recurrence in patients with axillary LN metastases.

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PURPOSE: To determine whether (18)F-FDG uptake in breast cancer correlates with immunohistochemically defined subtype and is able to predict molecular subtypes. METHODS: This retrospective study involved 306 patients with 308 mass-type invasive breast cancers (mean size 2.65 cm, range 1.0-15.0 cm) who underwent (18)F-FDG PET/CT before therapy. The correlations between primary tumour (18)F-FDG uptake on PET/CT, expressed as SUVmax, and clinicopathological findings and molecular subtype, i.e. luminal A, luminal B (HER2-negative), luminal B (HER2-positive), HER2-positive and triple-negative, were analysed. The predictors of these subtypes were investigated. RESULTS: The mean SUVmax of the 308 tumours was 5.33 ± 3.63 (range 1.15-19.01). Among the subtypes of the 308 tumours, 87 (28.2 %) were luminal A, 111 (36.0 %) were luminal B (HER2-negative), 31 (10.1 %) were luminal B (HER2-positive), 26 (8.4 %) were HER2-positive and 53 (17.2 %) were triple-negative, and the corresponding mean SUVmax were 3.41 ± 2.07 (range 1.18-14.30), 5.17 ± 3.52 (range 1.35-19.01), 6.57 ± 3.84 (range 1.42-15.58), 7.55 ± 3.63 (range 2.30-13.60) and 6.97 ± 4.17 (range 1.15-16.06), respectively. A cut-off value of 3.60 yielded 70.1 % sensitivity and 66.1 % specificity with an area under the receiver operating characteristics curve (AUC) of 0.734 for predicting that a tumour was of the luminal A subtype. A cut-off value of 6.75 yielded 65.4 % sensitivity and 75.2 % specificity with an AUC of 0.704 for predicting a HER2-positive subtype. CONCLUSION: SUVmax, a metabolic semiquantitative parameter, shows a significant correlation with the molecular subtype of breast cancer, and is useful for predicting the luminal A or HER2-positive subtype.

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Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non-small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

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PURPOSE: Neurokinin 1 (NK1) receptors have been implicated in depression, anxiety, and pain perception. Recently, it was shown that, in the human brain, a specific NK1 receptor-related signal was obtained with the novel radioligand, [¹¹C]R116301, using positron emission tomography. The purpose of this study was to evaluate various methods for quantifying specific [¹¹C]R116301 binding. METHODS: Two dynamic 90-min [¹¹C]R116301 scans, separated by 5 h, were performed in 11 healthy volunteers. In three patients, the second scan was performed after an oral blocking dose of 125 mg of aprepitant, whereas in the other eight, no intervention was performed (test-retest). Whole striatum was used as the tissue of interest, as it has the highest density of NK1 receptors. Cerebellum was used as the reference tissue. RESULTS: Reference tissue models were stable with the simplified reference tissue model (SRTM) performing best. Average (± standard deviation) SRTM-derived mean nondisplaceable binding potential (BP(ND)) of all (first) baseline scans was 0.64±0.31 (n=11), which reduced to -0.01±0.03 (n=3) after aprepitant administration. Test-retest results showed low variability (14.0±10.7%) and excellent reliability, as indicated by the intraclass correlation coefficient (0.93). The ratio of standardized uptake values of striatum and cerebellum minus 1, an approximation of BP(ND), showed very low variability (6.2±3.1%) with excellent reliability (intraclass correlation coefficient=0.98), and correlated well with SRTM-derived BP(ND) (R²=0.96). CONCLUSION: SRTM is the model of choice for quantifying [¹¹C]R116301 binding. Semiquantitative tissue ratios hold promise for routine clinical applications.

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PURPOSE: NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [(11)C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. PROCEDURES: Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. RESULTS: Baseline SUV ratios at 60-90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. CONCLUSION: These preliminary results indicate that [(11)C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain.

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OBJECTIVE: Noninvasive imaging by positron emission tomography (PET) of macrophages in inflamed joints of patients with rheumatoid arthritis (RA) may allow early detection of disease activity. We undertook this study to investigate whether rheumatoid synovitis can be visualized by PET using the tracer 11C-(R)-PK11195, which binds to peripheral benzodiazepine receptors (PBRs) on macrophages. METHODS: Knee joints of 11 RA patients with active arthritis of at least 1 knee joint were imaged with 11C-(R)-PK11195 PET. Tissue uptake of 11C-(R)-PK11195 was quantified. PET was followed by arthroscopy of the most inflamed knee joint of each RA patient. Synovial tissue samples were subjected to immunohistochemical staining. RESULTS: 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints than in joints with moderate or mild signs of inflammation. In addition, tracer uptake in contralateral uninflamed knee joints of RA patients was significantly higher than in uninflamed joints of control patients without inflammatory joint disease, suggesting the presence of subclinical disease activity. PET tracer uptake in joints correlated significantly with PBR staining in the sublining of synovial tissue. PBR staining correlated significantly with CD68 staining of macrophages. CONCLUSION: 11C-(R)-PK11195 PET imaging allows noninvasive in vivo imaging of macrophages in rheumatoid synovitis and possibly even in subclinical synovitis. Noninvasive visualization of macrophages may be useful both for detecting early synovitis and for monitoring synovitis activity during treatment.

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BACKGROUND: Recent epidemiological studies have shown that individuals with periodontitis have a significantly increased risk of developing coronary heart disease. In addition to conventional risk factors, chronic infection and subsequent production of systemic inflammatory markers may be associated with this increased risk. OBJECTIVES: The aim of the present study was to determine whether the presence of chronic periodontitis and subsequent periodontal treatment could influence the serum levels of C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-alpha (TNF-alpha) in a Japanese population. METHODS: Sera were obtained from 24 patients with moderate to advanced periodontitis at the baseline examination and at reassessment after completion of treatment. As a control, sera were also obtained from 21 subjects without periodontitis. High-sensitivity CRP (hs-CRP) was measured using nephelometry with a latex particle-enhanced immunoassay and interleukin-6 and TNF-alpha were determined by sensitive enzyme-linked immunosorbent assay. RESULTS: The levels of hs-CRP and interleukin-6 in the sera of this Japanese population seemed to be much lower than those reported in other populations. TNF-alpha on the other hand, demonstrated similar levels between this Japanese and other populations. Periodontal status demonstrated a significant improvement in all patients following treatment. There was a trend toward higher hs-CRP levels in patients at baseline compared with control subjects. Hs-CRP level tended to decrease with improvement of the periodontal condition following treatment and approached that of control subjects, although this decline was not statistically significant. interleukin-6 and TNF-alpha levels did not change following periodontal treatment. Furthermore, there was no difference in the serum levels of these inflammatory cytokines between patients either at baseline or at reassessment and control subjects. CONCLUSIONS: In this pilot study, we were unable to show that periodontal disease significantly affects the serum levels of systemic inflammatory markers. However, this does not necessarily mean that periodontitis does not contribute to the total burden of inflammation as there was a tendency for hs-CRP to decrease following successful periodontal treatment. Large-scale studies are clearly needed to determine the impact of periodontal disease on systemic inflammation.

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OBJECTIVES: The aim of this study was to elucidate whether the response of idiopathic dilated cardiomyopathy (DCM) patients to beta-blockers can be predicted by positron emission tomography with fluorine-18 fluoro-2-deoxyglucose (FDG-PET). BACKGROUND: Patients with DCM often have a poor prognosis, and it is important to predict their response to beta-blocker therapy, which may be effective in DCM. However, no accurate methods of predicting their response have been available. METHOD: In 22 DCM patients with reduced left ventricular (LV) systolic function, FDG-PET was performed. Uptake in the LV after glucose loading was evaluated based on the average global percent uptake of the injected dose (G%ID) and the coefficient of variance (CV) in 24 segments of the LV. Uptake during fasting was evaluated semiquantitatively on the basis of the total uptake score. The beta-blocker was administered, and LV function was monitored by echocardiography. The histologic findings were assessed in the 18 patients who underwent endomyocardial biopsy. RESULTS: The beta-blocker was effective in the majority of patients whose G%ID after glucose loading was >0.7%, and the sensitivity and specificity of G%ID as a predictor of beta-blocker efficacy were 83.3% and 90.0%, respectively. Percent CV did not predict efficacy. Four groups, defined on the basis of the FDG uptake score during fasting and G%ID after glucose loading, had distinctive histologic findings and outcomes. CONCLUSIONS: It has been shown that FDG-PET is a good predictor for the effectiveness of beta-blockers.

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OBJECTIVE: Left ventricular mass is an important determinant of diagnosis and prognosis in patients with heart disease. The aim of the present study was to validate measurement of the left ventricular mass index (LVMI) by quantitative gated myocardial SPECT (QGS) with 99mTc-tetrofosmin by comparing it with echocardiography. METHODS: QGS and M-mode echocardiography (Echo) were performed within one month of each other in 179 patients. M-mode echocardiography was carried out according to Devereux's method. QGS images were acquired one hour after injection of 99Tc-tetrofosmin at rest. Myocardial volume was defined as the volume between the endocardial and epicardial surface in the end-diastolic phase. LVMI (g/m2) was defined as myocardial volume divided by myocardial specific density and corrected for body surface area. QGS LVMI measurements were performed twice by the same observer and independently by two different observers. Regional hypoperfusion in the group of patients with old myocardial infarction (n = 26) was evaluated semiquantitatively on the basis of the total defect score on the resting 99mTc-tetrofosmin SPECT images. RESULTS: Among the patients as a whole QGS LVMI was significantly correlated with Echo LVMI (r = 0.96, p < 0.001). Intra-observer and inter-observer analyses showed significant reproducibility (r = 0.99 and r = 0.98, respectively, p < 0.001). In the patients with old myocardial infarction, but QGS LVMI was significantly lower than Echo LVMI (p < 0.001), and the magnitude of the underestimation was closely related to the severity of the perfusion defect on the resting SPECT images. CONCLUSIONS: Measurements of LVMI by 99mTc-tetrofosmin QGS are reproducible and consistent with echocardiograpic estimates. Underestimation in patients with severe perfusion defects must be taken into consideration.

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Inflammation and cell death are two important components of myocarditis. We evaluated the distribution of inflammation and apoptotic cell death in rats with autoimmune myocarditis using two radiotracers - technetium-99m Hynic-annexin V ((99m)Tc-annexin) as a marker of apoptotic cell death and carbon-14 deoxyglucose ((14)C-DG) as a marker of inflammation - in comparison with histologic findings. Three, 7 and 14 weeks after immunization with porcine cardiac myosin (acute, subacute, and chronic phases, respectively) (99m)Tc-annexin and (14)C-DG were injected. The uptake in the total heart was determined as the percentage of injected dose per gram (% ID/g) by tissue counting. Dual-tracer autoradiography with (99m)Tc-annexin and (14)C-DG was performed. The distribution of each of these agents was compared with the results of hematoxylin and eosin staining to identify areas of inflammation, and TUNEL staining to identify areas of apoptosis. Total cardiac uptake of (99m)Tc-annexin in the acute phase of myocarditis was significantly higher than that in normal rats (1.28%+/-0.30% vs 0.46%+/-0.01%; P<0.0001); it then decreased in the subacute phase and reached normal levels (0.56%+/-0.08% vs 0.60%+/-0.08%; P=NS). Total cardiac uptake of (14)C-DG in the acute phase of myocarditis was significantly higher than that in normal rats (2.78%+/-0.95% vs 1.02%+/-0.25%; P<0.0001); it then decreased in the subacute phase, but still remained higher than in controls (2.06%+/-0.52% vs 1.37%+/-0.46%; P<0.05). Using autoradiography and staining of tissue specimens, it was found that most histologic inflammatory foci corresponded to areas of high (14)C-DG uptake; some also corresponded to areas of high (99m)Tc-annexin uptake in the acute phase of myocarditis. (99m)Tc-annexin localization was strongly correlated with the number of TUNEL-positive cells (P<0.0001, r=0.83), but the uptake of (14)C-DG showed no relationship with it. There is a marked difference in the distribution of inflammation and apoptotic cell death in the myocardium of animals with immune myocarditis. These changes are mirrored by the localization of (14)C-DG and (99m)Tc-annexin. Sites of inflammation and zones of apoptotic cell death change over the course of immune myocarditis.

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BACKGROUND: The methyl-branched free fatty acid analog 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is metabolized more rapidly than 15-(p-iodophenyl)-3(beta)-(R,S)-methylpentadecanoic acid. This study investigates whether myocardial ischemic injury to beta-oxidation and viable myocardium can be detected with the use of 9MPA in a rat myocardial ischemia model. METHODS AND RESULTS: In the acute study the left coronary arteries were occluded for 15 or 45 minutes and then reperfused; the rats were killed after 2 hours. Iodine 125 and iodine 123 9MPA was injected 60 minutes (delayed images) and 3 minutes (early images), respectively, before the rats were killed. In the subacute study the left coronary arteries were either occluded for 45 minutes and then reperfused or occluded and not reperfused. One week later, I-125 and I-123 9MPA was injected 60 minutes and 3 minutes, respectively, before the rats were killed. The distribution of 9MPA was examined with the use of dual-tracer autoradiography. In the acute study the delayed images showed a higher uptake in viable regions at risk than in normal areas and nonviable regions. In the subacute study a difference in uptake between viable regions at risk and normal areas was visible on the early images, but this difference disappeared on the delayed images. CONCLUSIONS: 9MPA is a useful tracer for detecting viable regions of ischemic myocardium during acute and subacute disease stages.

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BACKGROUND: A number of studies have demonstrated prolonged left ventricular (LV) global dysfunction after exercise-induced ischemia in gated myocardial single photon emission tomography (SPECT) as a manifestation of exercise-induced stunning. This study investigated the residual effects of exercise on postexercise LV regional function and its implications on the detection of stunning in gated SPECT. METHODS AND RESULTS: Fifty-three subjects with known or suspected coronary artery disease and 10 control subjects underwent myocardial SPECT according to a same-day exercise-rest protocol. Both postexercise and resting images were gated and acquired 1 hour after injection of technetium 99m tetrofosmin. The LV global ejection fraction and segmental systolic wall thickening were quantitated with the use of an automatic program. Segmental perfusion was assessed semiquantitatively on summed nongated tomograms. Wall thickening index (WTI), the ratio of systolic wall thickening of a segment to that of a corresponding control segment, was significantly lower after exercise than at rest in the reversible defect (RD) segments (0.66 +/- 0.24 vs 0.78 +/- 0.24; P <.0001). In patients with exercise-induced ischemia, the difference in WTI between rest and after exercise was significantly greater in the RD segments, which represented ischemia, than in the non-RD segments. Postexercise WTIs were not different from the resting values in subjects with no perfusion abnormalities or who had fixed defects (infarction). Significant postexercise dysfunction was present in 44% of the RD segments, compared with 5% of the normal and 3% of the fixed defect segments. Postexercise segmental dysfunction was correlated with the segmental reversibility score, the difference in defect scores between exercise and rest images (n = 82, Spearman rank correlation coefficient = -0.78, P <.0001). Among 19 patients with ischemia, 9 (47%) exhibited concurrent segmental and global dysfunction, but segmental dysfunction persisted in the absence of global dysfunction in 4 additional patients (21%). CONCLUSIONS: Significant postexercise LV regional dysfunction, consistent with the concept of stunning, occurs in the region of severe ischemia. The incidence and magnitude of regional stunning are determined by the severity of ischemia. For the detection of stunning in gated SPECT, LV regional dysfunction may be more sensitive than global dysfunction.

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OBJECT: This study was designed to assess the value of gated SPECT Tc-99m-tetrofosmin (TF) wall thickening (WT) in addition to TF exercise (Ex)/rest myocardial SPECT, in comparison with F-18 fluorodeoxyglucose (FDG)-PET. METHODS: The study population consisted of 33 patients with old myocardial infarction (27 men and 6 women; mean age, 62 +/- 8 years old). All patients underwent Ex/rest TF SPECT and glucose loading FDG-PET. Polar map images of Ex/rest TF were generated and divided into 24 segments for further analysis. We classified LV segments according to the exercise-rest perfusion scintigraphy. LV segments with less than 70% of the maximum TF activity on the exercise image were defined as stress-induced defects. Among these, the segments whose TF activity increased by 10% from exercise to rest images or exceeded 70% of the maximum uptake were defined as reversible (viable) defects. The remaining defects on the rest image were irreversible (non-viable) defect segments, and were considered for viability study on the basis of %WT. %WT was calculated according to the standard method: [(counts ES - counts ED)/counts ED] x 100. A viable segment on gated SPECT was defined as a segment whose %WT exceeded the lower limit of the normal value (mean - SD). PET viability was defined as FDG uptake exceeding 50% of the maximum count. RESULTS: Among the 792 segments evaluated in the 33 patients studied, there were 689 PET viable segments. Of the 689 segments analyzed, 198 (29%) were identified as having defects on Ex images. Among these defects, 55 (8%) were reversible or partially reversible, as evidenced by rest images, and 143 (21%) were irreversible. Of the irreversible segments on Ex/rest images, 106 (15%) demonstrated no apparent WT by gated TF SPECT, whereas 37 (6%) segments with irreversible defects did have apparent WT. Overall, the sensitivity of Ex/rest TF perfusion imaging was 79%. Sensitivity was improved from 79% to 85% by combining %WT and perfusion data, but specificity was reduced from 70% to 56%. CONCLUSION: %WT evaluated from gated TF imaging enhanced myocardial viability assessment in comparison with FDG-PET.

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