Translocator protein imaging with 18F-FEDAC-positron emission tomography in rabbit atherosclerosis and its presence in human coronary vulnerable plaques.

BACKGROUND AND AIMS: This study aimed to investigate whether N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide (18F-FEDAC), a probe for translocator protein (TSPO), can visualize atherosclerotic lesions in rabbits and whether TSPO is localized in human coronary plaques. METHODS: 18F-FEDAC-PET of a rabbit model of atherosclerosis induced by a 0.5% cholesterol diet and balloon injury of the left carotid artery (n = 7) was performed eight weeks after the injury. The autoradiography intensity of 18F-FEDAC in carotid artery tissue sections was measured, and TSPO expression was evaluated immunohistochemically. TSPO expression was examined in human coronary arteries obtained from autopsy cases (n = 16), and in human coronary plaques (n = 12) aspirated from patients with acute myocardial infarction (AMI). RESULTS: 18F-FEDAC-PET visualized the atherosclerotic lesions in rabbits as high-uptake areas, and the standard uptake value was higher in injured arteries (0.574 ± 0.24) than in uninjured arteries (0.277 ± 0.13, p < 0.05) or myocardium (0.189 ± 0.07, p < 0.05). Immunostaining showed more macrophages and more TSPO expression in atherosclerotic lesions than in uninjured arteries. TSPO was localized in macrophages, and arterial autoradiography intensity was positively correlated with macrophage concentration (r = 0.64) and TSPO (r = 0.67). TSPO expression in human coronary arteries was higher in AMI cases than in non-cardiac death, or in the vulnerable plaques than in early or stable lesions, respectively. TSPO was localized in macrophages in all aspirated coronary plaques with thrombi. CONCLUSIONS: 18F-FEDAC-PET can visualize atherosclerotic lesions, and TSPO-expression may be a marker of high-risk coronary plaques.

Clinical practice guidelines for high-resolution breast PET, 2019 edition.

Breast positron emission tomography (PET) has had insurance coverage when performed with conventional whole-body PET in Japan since 2013. Together with whole-body PET, accurate examination of breast cancer and diagnosis of metastatic disease are possible, and are expected to contribute significantly to its treatment planning. To facilitate a safer, smoother, and more appropriate examination, the Japanese Society of Nuclear Medicine published the first edition of practice guidelines for high-resolution breast PET in 2013. Subsequently, new types of breast PET have been developed and their clinical usefulness clarified. Therefore, the guidelines for breast PET were revised in 2019. This article updates readers as to what is new in the second edition. This edition supports two different types of breast PET depending on the placement of the detector: the opposite-type (positron emission mammography; PEM) and the ring-shaped type (dedicated breast PET; dbPET), providing an overview of these scanners and appropriate imaging methods, their clinical applications, and future prospects. The name "dedicated breast PET" from the first edition is widely used to refer to ring-shaped type breast PET. In this edition, "breast PET" has been defined as a term that refers to both opposite- and ring-shaped devices. Up-to-date breast PET practice guidelines would help provide useful information for evidence-based breast imaging.

Effects of Repeated 131I-Meta-Iodobenzylguanidine Radiotherapy on Tumor Size and Tumor Metabolic Activity in Patients with Metastatic Neuroendocrine Tumors.

131I-meta-iodobenzylguanidine (131I-MIBG) radiotherapy has shown some survival benefits in metastatic neuroendocrine tumors (NETs). European Association of Nuclear Medicine clinical guidelines for 131I-MIBG radiotherapy suggest a repeated treatment protocol, although none currently exists. The existing single-high-dose 131I-MIBG radiotherapy (444 MBq/kg) has been shown to have some benefits for patients with metastatic NETs. However, this protocol increases adverse effects and requires alternative therapeutic approaches. Therefore, the aim of this study was to evaluate the effects of repeated 131I-MIBG therapy on tumor size and tumor metabolic response in patients with metastatic NETs. Methods: Eleven patients with metastatic NETs (aged 49.2 ± 16.3 y) prospectively received repeated 5,550-MBq doses of 131I-MIBG therapy at 6-mo intervals. In total, 31 treatments were performed. The mean number of treatments was 2.8 ± 0.4, and the cumulative 131I-MIBG dose was 15,640.9 ± 2,245.1 MBq (286.01 MBq/kg). Tumor response was observed by CT and 18F-FDG PET or by 18F-FDG PET/CT before and 3-6 mo after the final 131I-MIBG treatment. Results: On the basis of the CT findings with RECIST, 3 patients showed a partial response and 6 patients showed stable disease. The remaining 2 patients showed progressive disease. Although there were 2 progressive-disease patients, analysis of all patients showed no increase in summed length diameter (median, 228.7 mm [interquartile range (IQR), 37.0-336.0 mm] to 171.0 mm [IQR, 38.0-270.0 mm]; P = 0.563). In tumor region-based analysis with partial-response and stable-disease patients (n = 9), 131I-MIBG therapy significantly reduced tumor diameter (79 lesions; median, 16 mm [IQR, 12-22 mm] to 11 mm [IQR, 6-16 mm]; P < 0.001). Among 5 patients with hypertension, there was a strong trend toward systolic blood pressure reduction (P = 0.058), and diastolic blood pressure was significantly reduced (P = 0.006). Conclusion: Eighty-two percent of metastatic NET patients effectively achieved inhibition of disease progression, with reduced tumor size and reduced metabolic activity, through repeated 131I-MIBG therapy. Therefore, this relatively short-term repeated 131I-MIBG treatment may have potential as one option in the therapeutic protocol for metastatic NETs. Larger prospective studies with control groups are warranted.

Validation of regional myocardial blood flow quantification using three-dimensional PET with rubidium-82: repeatability and comparison with two-dimensional PET data acquisition.

INTRODUCTION: Three-dimensional (3D) data acquisition is now standard on PET/computed tomography scanners. The aim of this study was to evaluate the repeatability of myocardial blood flow (MBF) estimation with rubidium-82 (Rb) 3D PET and to validate regional MBF measurements by comparison with two-dimensional (2D) PET. PATIENTS AND METHODS: Fifteen healthy individuals (31.6 ± 11.4 years old) were enrolled for the evaluation of the short-term repeatability of rest 3D MBF quantification. Another 19 healthy individuals (35.3 ± 12.6 years old) underwent rest and pharmacological stress PET using 2D and 3D data acquisition within a 1-month interval. The injected dose was 1500 MBq for 2D and 555 MBq for 3D PET acquisition. RESULTS: MBF at rest showed good repeatability [whole left ventricular MBF; 0.54 ± 0.13 vs. 0.52 ± 0.13 mL/min/g, P = 0.98]. Rest MBF, stress MBF, and myocardial flow reserve (MFR) were not significantly different between 3D and 2D data acquisition. 3D MBF correlated well with 2D MBF over a wide flow range for both whole left ventricular (r = 0.97, P < 0.0001) and regional values (r = 0.61, P < 0.0001). CONCLUSION: MBF measured with 3D PET showed very good test-retest repeatability. Whole left ventricular and regional MBF measurements obtained using lower Rb-dose 3D PET were highly correlated over a wide range with those from 2D PET. Therefore, MBF with 3D PET can be applied using a lower Rb dosage in clinical settings with reduced radiation exposure.

Quantification of myocardial blood flow with 11C-hydroxyephedrine dynamic PET: comparison with 15O-H2O PET.

BACKGROUND: 11C-hydroxyephedrine (HED) PET has been used to evaluate the myocardial sympathetic nervous system (SNS). Here we sought to establish a simultaneous approach for quantifying both myocardial blood flow (MBF) and the SNS from a single HED PET scan. METHODS: Ten controls and 13 patients with suspected cardiac disease were enrolled. The inflow rate of 11C-HED (K1) was obtained using a one-tissue-compartment model. We compared this rate with the MBF derived from 15O-H2O PET. In the controls, the relationship between K1 from 11C-HED PET and the MBF from 15O-H2O PET was linked by the Renkin-Crone model. RESULTS: The relationship between K1 from 11C-HED PET and the MBF from 15O-H2O PET from the controls' data was approximated as follows: K1  =  (1 - 0.891 * exp(- 0.146/MBF)) * MBF. In the validation set, the correlation coefficient demonstrated a significantly high relationship for both the whole left ventricle (r = 0.95, P < 0.001) and three coronary territories (left anterior descending artery: r = 0.96, left circumflex artery: r = 0.81, right coronary artery: r =  0.86; P < 0.001, respectively). CONCLUSION: 11C-HED can simultaneously estimate MBF and sympathetic nervous function without requiring an additional MBF scan for assessing mismatch areas between MBF and SNS.

[A Case of WDHA Water Diarrhea Hypokalemia Achlorhydria Syndrome that Developed after Multimodal Therapy for Retroperitoneal Paraganglioma].

A 45-year-old woman visited a local clinic with left-flank abdominal pain. Abdominal computed tomography (CT) revealed a tumor 20 cm in diameter in the left adrenal gland. She was referred to our hospital for further treatment. No endocrinological abnormality was detected on either serum or urine examination. CT and haematology findings led to a preoperative diagnosis of primary adrenal carcinoma, and we performed a left adrenalectomy. Histopathological examination revealed a paraganglioma with intact adrenal gland. Therefore we diagnosed this case as primary retroperitoneal paraganglioma. Six months after the surgery, she developed peritoneal dissemination including bilateral ovarian metastases. After cytoreductive metastasectomy, she received 131I-meta-iodobenzylguanidine (MIBG) radiotherapy. During the following five-year follow-up, MIBG radiotherapy in conjunction with cytoreductive metastasectomy (3 surgeries and 6 sessions of 131I-MIBG radiotherapy) was performed, aiming at disease control. Five years after the initial surgery, liver, lung, and intra-peritoneal dissemination progressed. Thereafter, she developed severe diarrhea, hypokalemia, and metabolic acidosis with an elevated level of vasoactive intestional peptide, which was consistent with water diarrhea, hypokalemia, achlorhydria (WDHA) syndrome. Despite intensive treatments such as with a somatostatin analogue, she died two months after the onset of this syndrome.

Preclinical Evaluation of the Acute Radiotoxicity of the α-Emitting Molecular-Targeted Therapeutic Agent 211At-MABG for the Treatment of Malignant Pheochromocytoma in Normal Mice.

The α-emitter 211At-labeled meta-astatobenzylguanidine (211At-MABG) has a strong antitumor effect on pheochromocytoma xenograft tumors and holds great promise as a new therapeutic option for malignant pheochromocytoma. To evaluate the acute radiation-related toxicity of 211At-MABG, we conducted biodistribution and dosimetry studies of 211At-MABG in ICR mice to estimate the doses absorbed by organs. We determined the maximum tolerated doses (MTD) of 211At-MABG on the basis of body weight loss and assessed the acute radiation-related toxicity induced by MTD administration on the basis of organ weights, histologic features, hematologic indices, and biochemical indices. The biodistribution and dosimetry studies of α-emitting 211At-MABG revealed high doses absorbed by most organs except the brain in ICR mice. The administration of 1.1, 2.2, and 3.3 MBq of 211At-MABG induced transient body weight loss, and 4.4 MBq of 211At-MABG induced unrecoverable body weight loss; thus, the MTD was 3.3 MBq for ICR mice. Although by day 5 the administration of 3.3 MBq had induced some radiation-related toxicity symptoms-such as body weight loss and leucopenia, which are generally observed in radiation therapy including ß--emitting radiopharmaceuticals-the mice had recovered by day 28. We observed no unexpected severe toxicity in ICR mice despite the high absorbed doses in most organs, especially the thyroid, heart, stomach, and adrenal glands. Our findings suggest that therapeutic treatments with appropriate doses of 211At-MABG estimated by dosimetry in each patient could be tolerated, although lower doses may initially be necessary to ensure patient safety in the first-in-human study.

Early therapeutic effects of adaptive servo-ventilation on cardiac sympathetic nervous function in patients with heart failure evaluated using a combination of 11C-HED PET and 123I-MIBG SPECT.

RATIONALE: Adaptive servo-ventilation (ASV), a novel respiratory support therapy for sleep disorders, may improve cardiac function in heart failure (HF). However, the reasons that ASV improves cardiac function have not been fully studied especially in sympathetic nervous function (SNF). The purpose of the present study was to investigate the effects of ASV therapy on cardiac SNF in patients with HF. METHODS: We evaluated ASV therapeutic effects before and 6 months after ASV therapy in 9 HF patients [57.3 ± 17.3 years old, left ventricular ejection fraction (LVEF) 36.1 ± 16.7%]. We performed echocardiography, polysomnography, biomarkers, 11C-hydroxyephedrine (HED) PET as a presynaptic function marker and planar 123I-metaiodobenzylguanidine (MIBG) to evaluate washout rate. RESULTS: ASV therapy reduced apnea-hypopnea index (AHI) and improved plasma brain natriuretic peptide (BNP) concentration. In 123I-MIBG imaging, the early heart/mediastinum (H/M) ratio increased after ASV therapy (2.19 ± 0.58 to 2.40 ± 0.67; P = 0.045). Washout rate did not change (23.8 ± 7.3% to 23.8 ± 8.8%; P = 0.122). Global 11C-HED retention index (RI) improved from 0.068 ± 0.033/s to 0.075 ± 0.034/s (P = 0.029). CONCLUSIONS: ASV reduced AHI and improved BNP. ASV might initially improve presynaptic cardiac sympathetic nervous function in HF patients after 6 months of treatment.

Use of 18F-FDG PET/CT texture analysis to diagnose cardiac sarcoidosis.

PURPOSE: 18F-fluorodeoxyglocose positron emission tomography (FDG PET) plays a significant role in the diagnosis of cardiac sarcoidosis (CS). Texture analysis is a group of computational methods for evaluating the inhomogeneity among adjacent pixels or voxels. We investigated whether texture analysis applied to myocardial FDG uptake has diagnostic value in patients with CS. METHODS: Thirty-seven CS patients (CS group), and 52 patients who underwent FDG PET/CT to detect malignant tumors with any FDG cardiac uptake (non-CS group) were studied. A total of 36 texture features from the histogram, gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), gray-level zone size matrix (GLZSM) and neighborhood gray-level difference matrix (NGLDM), were computed using polar map images. First, the inter-operator and inter-scan reproducibility of the texture features of the CS group were evaluated. Then, texture features of the patients with CS were compared to those without CS lesions. RESULTS: Twenty-eight of the 36 texture features showed high inter-operator reproducibility with intraclass correlation coefficients (ICCs) over 0.80. In addition, 17 of the 36 showed high inter-scan reproducibility with ICCs over 0.80. The SUVmax showed no difference between the CS and non-CS group [7.36 ± 2.77 vs. 8.78 ± 4.65, p = 0.45, area under the curve (AUC) = 0.60]. By contrast, 16 of the 36 texture features could distinguish CS from non-CS grsoup with AUC > 0.80. Multivariate logistic regression analysis after hierarchical clustering concluded that long-run emphasis (LRE; P = 0.0004) and short-run low gray-level emphasis (SRLGE; P = 0.016) were significant independent factors that could distinguish between the CS and non-CS groups. Specifically, LRE was significantly higher in CS than in non-CS (30.1 ± 25.4 vs. 11.4 ± 4.6, P < 0.0001), with high diagnostic ability (AUC = 0.91), and had high inter-operator reproducibility (ICC = 0.98). CONCLUSIONS: The texture analysis had high inter-operator and high inter-scan reproducibility. Some of texture features showed higher diagnostic value than SUVmax for CS diagnosis. Therefore, texture analysis may have a role in semi-automated systems for diagnosing CS.

How do we establish cardiac sympathetic nervous system imaging with 123I-mIBG in clinical practice? Perspectives and lessons from Japan and the US.

Cardiac denervation is associated with progressive left ventricular (LV) dysfunction, ventricular arrhythmias, and sudden cardiac death (SCD) in heart failure (HF). In this regard, it is important to evaluate cardiac-specific sympathetic nervous system (SNS) function. The radiotracer Iodine-123 meta-iodobenzylguanidine (123I-mIBG) can noninvasively evaluate pre-synaptic SNS function. Recent multicenter trials have shown 123I-mIBG to have strong predictive value for fatal arrhythmias and cardiac death in HF. 123I-mIBG was initially developed in the USA in the 1970s. In 1992, the Japanese Ministry of Health and Labour approved 123I-mIBG for the assessment of cardiac function. Following approval, the Japanese nuclear cardiology community developed 123I-mIBG imaging services in various medical centers. Japanese groups have been trying to establish the clinical utility of 123I-mIBG and standardize parameters for data acquisition and image analysis. The US Food and Drug Administration (FDA) has approved clinical use of 123I-mIBG for cardiac and non-cardiac imaging. However, clinical use of 123I-mIBG in the US has been very limited. The number of 123I-mIBG studies in Japan has also been limited. There are similarities and differences between the two countries. To establish the clinical utility of 123I-mIBG in both countries, it is important to characterize the situations of 123I-mIBG in each.

Do TSH, FT3, and FT4 Impact BAT Visualization of Clinical FDG-PET/CT Images?

Objective: We retrospectively analyzed activated BAT visualization on FDG-PET/CT in patients with various conditions and TH levels to clarify the relationships between visualization of BAT on FDG-PET/CT and the effect of TH. Methods: Patients who underwent clinical FDG-PET/CT were reviewed and we categorized patients into 5 groups: (i) thyroid hormone withdrawal (THW) group; (ii) recombinant human thyrotropin (rhTSH) group; (iii) hypothyroidism group; (iv) hyperthyroidism group; and (v) BAT group. A total of sixty-two FDG-PET/CT imaging studies in fifty-nine patients were performed. To compare each group, gender; age; body weight; serum TSH, FT3, and FT4 levels; and outside temperature were evaluated. Results: No significant visualization of BAT was noted in any of the images in the THW, rhTSH, hypothyroidism, and hyperthyroidism groups. All patients in the BAT group were in a euthyroid state. When the BAT-negative and BAT-positive patient groups were compared, it was noted that the minimum and maximum temperature on the day of the PET study and maximum temperature of the one day before the PET study were significantly lower in BAT-positive group than in all those of other groups. Conclusions: Elevated TSH condition before RIT, hyperthyroidism, or hypothyroidism did not significantly impact BAT visualization of clinical FDG-PET/CT images.

Antitumor effects of radionuclide treatment using α-emitting meta-211At-astato-benzylguanidine in a PC12 pheochromocytoma model.

PURPOSE: Therapeutic options for patients with malignant pheochromocytoma are currently limited, and therefore new treatment approaches are being sought. Targeted radionuclide therapy provides tumor-specific systemic treatments. The ß-emitting radiopharmaceutical meta-131I-iodo-benzylguanidine (131I-MIBG) provides limited survival benefits and has adverse effects. A new generation of radionuclides for therapy using α-particles including meta-211At-astato-benzylguanidine (211At-MABG) are expected to have strong therapeutic effects with minimal side effects. However, this possibility has not been evaluated in an animal model of pheochromocytoma. We aimed to evaluate the therapeutic effects of the α-emitter 211At-MABG in a pheochromocytoma model. METHODS: We evaluated tumor volume-reducing effects of 211At-MABG using rat pheochromocytoma cell line PC12 tumor-bearing mice. PC12 tumor-bearing mice received intravenous injections of 211At-MABG (0.28, 0.56, 1.11, 1.85, 3.70 and 5.55 MBq; five mice per group). Tumor volumes were evaluated for 8 weeks after 211At-MABG administration. The control group of ten mice received phosphate-buffered saline. RESULTS: The 211At-MABG-treated mice showed significantly lower relative tumor growth during the first 38 days than the control mice. The relative tumor volumes on day 21 were 509.2% ± 169.1% in the control mice and 9.6% ± 5.5% in the mice receiving 0.56 MBq (p < 0.01). In addition, the mice treated with 0.28, 0.56 and 1.11 MBq of 211At-MABG showed only a temporary weight reduction, with recovery in weight by day 10. CONCLUSION: 211At-MABG exhibited a strong tumor volume-reducing effect in a mouse model of pheochromocytoma without weight reduction. Therefore, 211At-MABG might be an effective therapeutic agent for the treatment of malignant pheochromocytoma.

Correction to: Radiopharmaceutical tracers for cardiac imaging.

Regrettably the original version of the above article contained errors in the three chemical structures presented in the 'Atherosclerosis imaging' section of Table 5, namely: 99mTc annexin V, 68Ga DOTATATE, and 64Cu DOTATATE; the chemical structures have been corrected in Table presented here. In addition, the radiopharmaceutical for isotope 67Ga has been corrected to 67Ga citrate, and many of the radiopharmaceuticals presented at the end of the table have been corrected.

Radiopharmaceutical tracers for cardiac imaging.

Cardiovascular disease (CVD) is the leading cause of death and disease burden worldwide. Nuclear myocardial perfusion imaging with either single-photon emission computed tomography or positron emission tomography has been used extensively to perform diagnosis, monitor therapies, and predict cardiovascular events. Several radiopharmaceutical tracers have recently been developed to evaluate CVD by targeting myocardial perfusion, metabolism, innervation, and inflammation. This article reviews old and newer used in nuclear cardiac imaging.

Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts.

Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq × 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of 64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease.

Absolute quantification of myocardial blood flow.

With the increasing availability of positron emission tomography (PET) myocardial perfusion imaging, the absolute quantification of myocardial blood flow (MBF) has become popular in clinical settings. Quantitative MBF provides an important additional diagnostic or prognostic information over conventional visual assessment. The success of MBF quantification using PET/computed tomography (CT) has increased the demand for this quantitative diagnostic approach to be more accessible. In this regard, MBF quantification approaches have been developed using several other diagnostic imaging modalities including single-photon emission computed tomography, CT, and cardiac magnetic resonance. This review will address the clinical aspects of PET MBF quantification and the new approaches to MBF quantification.

Cardiac sympathetic nervous system imaging with 123I-meta-iodobenzylguanidine: Perspectives from Japan and Europe.

Cardiac sympathetic nervous system dysfunction is closely associated with risk of serious cardiac events in patients with heart failure (HF), including HF progression, pump-failure death, and sudden cardiac death by lethal ventricular arrhythmia. For cardiac sympathetic nervous system imaging, 123I-meta-iodobenzylguanidine (123I-MIBG) was approved by the Japanese Ministry of Health, Labour and Welfare in 1992 and has therefore been widely used since in clinical settings. 123I-MIBG was also later approved by the Food and Drug Administration (FDA) in the United States of America (USA) and it was expected to achieve broad acceptance. In Europe, 123I-MIBG is currently used only for clinical research. This review article is based on a joint symposium of the Japanese Society of Nuclear Cardiology (JSNC) and the American Society of Nuclear Cardiology (ASNC), which was held in the annual meeting of JSNC in July 2016. JSNC members and a member of ASNC discussed the standardization of 123I-MIBG parameters, and clinical aspects of 123I-MIBG with a view to further promoting 123I-MIBG imaging in Asia, the USA, Europe, and the rest of the world.