Search

Abstract This study aimed to compare tumor lesion detectability and diagnostic accuracy of whole-body magnetic resonance imaging (WB-MRI) and radioiodine-labeled meta-iodo-benzylguanidine (mIBG) imaging techniques in patients with metastatic pheochromocytoma and paraganglioma (PPGL). This retrospective study included 13 patients had pheochromocytoma and 5 had paraganglioma, who were all suspected of having metastatic tumors. Each patient underwent WB-MRI and 123I-mIBG as a pretreatment screening for 131I-mIBG therapy. Two expert reviewers evaluated WB-MRI, 123I-mIBG images, and post-therapy 131I-mIBG images for the presence of metastatic lesions in the lungs, bones, liver, lymph nodes, and other organs. Diagnostic measures for detecting metastatic lesions, including sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristics (ROC)—area under the curve (AUC), were calculated for each imaging technique. We analyzed WB-MRI images for detecting metastatic lesions, which demonstrated sensitivity, specificity, accuracy, PPV, NPV, and AUC of 82%, 97%, 90%, 96%, 86%, and 0.92, respectively. These values were 83%, 95%, 89%, 94%, 86%, and 0.90 in 123I-mIBG images and 85%, 92%, 89%, 91%, 87%, and 0.91 in post-therapy 131I-mIBG images, respectively. Our results reveal the comparable diagnostic accuracy of WB-MRI to one of the mIBG images.

Abstract DNA double-strand breaks (DSBs) are considered the most relevant lesions to the DNA damage of ionizing radiation (IR), and γ-H2AX foci in peripheral blood lymphocytes are regarded as an adequate marker for DSB quantitative studies. This study aimed to investigate IR-induced DNA damage in mice through γ-H2AX fluorescence analyses by flow cytometry (FCM). The levels of γ-H2AX in CD4/CD8/B220-positive lymphocytes were quantified by FCM through mean fluorescence intensity (MFI) values. Peripheral venous blood samples were collected for evaluation, and all the control groups were restrained from irradiation. For external irradiation experiments, the dose-dependency of MFI values and temporal alternations were assessed both in vitro and in vivo. External radiation exposure damage was positively correlated with the absorbed radiation dose, and the lymphocyte recovered from damage within 3 days. I-131 sodium iodide solution (74 MBq) was injected into the mice intraperitoneally for internal irradiation experiments. Gamma counting and γH2AX foci analyses were performed at 1 h and 24 h by the group. The blood-to-blood S values (S blood←blood) were applied for the blood-absorbed dose estimation. Internal low-dose-irradiation-induced damage was proved to recover within 24 h. The FCM method was found to be an effective way of quantitatively assessing IR-induced DNA damage.

Abstract The foot exercises “rock-paper-scissors” and “towel gathering” are widely used in patients with lower limb disorders; however, there are no detailed reports on muscle activity during such training. We quantitatively evaluated the difference in skeletal muscle activity between the two exercises using positron emission tomography. Eight university student athletes were included. Four participants each were assigned to the foot rock-paper-scissors and towel gathering groups. Participants in each group underwent continuous training for 15 min, and received an intravenous injection of 18F-fluorodeoxyglucose. After retraining for 15 min, participants rested for 45 min. Regions of interest were defined in 25 muscles. The standardized uptake value (SUV) in the trained limb was compared with that in the non-trained control limb. SUVs increased in four skeletal muscles (tibialis anterior, peroneus brevis, extensor hallucis brevis, and abductor hallucis) in the rock-paper-scissors group, and in four muscles (flexor digitorum longus, extensor hallucis brevis, extensor digitorum brevis, and quadratus plantae) in the towel gathering group. Thus, foot rock-paper-scissors and towel gathering involved skeletal muscles related to the medial longitudinal arch and toe grip strength, respectively. Given that the two exercises target different skeletal muscles, they should be taught and implemented according to their respective purposes.

Abstract The use of effective shielding materials against radiation is important among medical staff in nuclear medicine. Hence, the current study investigated the shielding effects of a commercially available tungsten apron using gamma ray measuring instruments. Further, the occupational radiation exposure of nurses during 131I-meta-iodo-benzyl-guanidine (131I-MIBG) therapy for children with high-risk neuroblastoma was evaluated. Attachable tungsten shields in commercial tungsten aprons were set on a surface-ray source with 131I, which emit gamma rays. The mean shielding rate value was 0.1 ± 0.006 for 131I. The shielding effects of tungsten and lead aprons were evaluated using a scintillation detector. The shielding effect rates of lead and tungsten aprons against 131I was 6.3% ± 0.3% and 42.1% ± 0.2% at 50 cm; 6.1% ± 0.5% and 43.3% ± 0.3% at 1 m; and 6.4% ± 0.9% and 42.6% ± 0.6% at 2 m, respectively. Next, we assessed the occupational radiation exposure during 131I-MIBG therapy (administration dose: 666 MBq/kg, median age: 4 years). The total occupational radiation exposure dose per patient care per 131I-MIBG therapy session among nurses was 0.12 ± 0.07 mSv. The average daily radiation exposure dose per patient care among nurses was 0.03 ± 0.03 mSv. Tungsten aprons had efficient shielding effects against gamma rays and would be beneficial to reduce radiation exposures per patient care per 131I-MIBG therapy session.

Abstract Background Since three-dimensional segmentation of cardiac region in 123I-metaiodobenzylguanidine (MIBG) study has not been established, this study aimed to achieve organ segmentation using a convolutional neural network (CNN) with 123I-MIBG single photon emission computed tomography (SPECT) imaging, to calculate heart counts and washout rates (WR) automatically and to compare with conventional quantitation based on planar imaging. Methods We assessed 48 patients (aged 68.4 ± 11.7 years) with heart and neurological diseases, including chronic heart failure, dementia with Lewy bodies, and Parkinson's disease. All patients were assessed by early and late 123I-MIBG planar and SPECT imaging. The CNN was initially trained to individually segment the lungs and liver on early and late SPECT images. The segmentation masks were aligned, and then, the CNN was trained to directly segment the heart, and all models were evaluated using fourfold cross-validation. The CNN-based average heart counts and WR were calculated and compared with those determined using planar parameters. The CNN-based SPECT and conventional planar heart counts were corrected by physical time decay, injected dose of 123I-MIBG, and body weight. We also divided WR into normal and abnormal groups from linear regression lines determined by the relationship between planar WR and CNN-based WR and then analyzed agreement between them. Results The CNN segmented the cardiac region in patients with normal and reduced uptake. The CNN-based SPECT heart counts significantly correlated with conventional planar heart counts with and without background correction and a planar heart-to-mediastinum ratio (R 2 = 0.862, 0.827, and 0.729, p

Abstract The 123I-labeled meta-iodobenzylguanidine (MIBG) is an analogue of noradrenaline that can evaluate cardiac sympathetic activity in scintigraphy. Quantitative analysis of 123I-MIBG images has been verified in patients with heart failure and neurodegenerative diseases. However, quantitative results differ due to variations in scintigraphic imaging procedures. Here, we created and assessed the clinical feasibility of a calibration method for 123I-MIBG imaging. The characteristics of scintigraphic imaging systems were determined using an acrylic calibration phantom to generate a multicenter phantom imaging database. Calibration factors corresponding to the scintigraphic imaging procedures were calculated from the database and applied to a clinical study. The results of this study showed that the calibrated analysis eliminated inter-institutional differences among normal individuals. In summary, our standardization methodology for 123I-MIBG scintigraphy could provide the basis for improved diagnostic precision and better outcomes for patients.

Summary: Medication-related osteonecrosis of the jaw (MRONJ) is a significant side effect of antiresorptive and antiangiogenic drugs. Since MRONJ is intractable, early detection is the best way to limit progression. Bone scintigraphy and 18F- fluorodeoxyglucose positron-emission tomography can detect minimal and subclinical changes in bones earlier than conventional radiological modalities. A differential diagnosis including MRONJ is recommended when abnormally high uptakes are incidentally detected in the jaws of patients who have bone metastases. Quantitative analysis of uptakes, such as bone scan index of the jaw using neural network analysis and maximum standardized uptake value, could differentiate MRONJ from common dental diseases and be useful for the early detection and risk assessment of MRONJ. Keyword: Bone scintigraphy, Bone scan index, Computer-aided diagnosis, FDG PET, Osteonecrosis, Jaw

Objective(s): Single-photon emission computed tomography (SPECT) using metaiodobenzylguanidine (MIBG) is an important diagnostic tool for the treatment of refractory pheochromocytoma and paraganglioma (PPGL). Owing to the difficulty of SPECT quantification, the tumour-to-background ratio (TBR) is used to assess disease activity. However, the utility of TBR is limited owing to the background setting. A quantification technique of SPECT/computed tomography (CT) would facilitate image interpretation. This study aimed to assess the relationship between 123I-MIBG maximum standardized uptake value (SUVmax) and TBR and levels of urinary catecholamines and metabolites in patients with refractory PPGL. Methods: This study included 15 patients with refractory PPGL who underwent 131I-MIBG therapy. Overall, 27 123I-MIBG SPECT/CT images were acquired before and after the therapy. Lesions observed on whole-body images were analysed; the maximum number of lesions per scan was 10. 123I-MIBG SUVmax was semi-automatically calculated using Q. Metrix package (GE Healthcare). TBR was manually calculated according to the following formula: (max count in lesion − max count in background)/max count in background. Background was set in the contralateral area. When a background region of interest could not be set in the area, it was set in the thigh area. Urine was sampled for 24 h to measure catecholamine and metabolite levels. Increases of ≥3-fold were considered abnormal. TBR, 123I-MIBG SUVmax and urinary catecholamine and metabolite levels were compared using linear regression analysis. Results: All patients had MIBG-avid lesions, as seen on 123I-MIBG SPECT/CT. A significant relationship between 123I-MIBG SUVmax and TBR was observed (correlation coefficient [r] =0.84, P < 0.0001). In 27 SPECT/CT examinations, normetanephrine (NMN) level was abnormally increased in 51% (14/27), but other catecholamine and other metabolites were abnormally increased in < 26% (7/27). 123I-MIBG SUVmax strongly correlated with NMN (r=0.76, P < 0.01) and log NMN (r=0.74, P < 0.01). Conclusion: 123I-MIBG SUVmax demonstrated similar trends as TBR and reflected urinary NMN in patients with refractory PPGL. Semi-automatic quantification of SPECT/CT could be a useful tool for the evaluation of disease activity

Abstract Background Diagnosis of the cause of low back pain in the presence of degenerative spine disease using conventional imaging techniques, especially in elderly individuals, is challenging. Our aim was to describe our use of bone scintigraphy with single photon emission computed tomography (bone SPECT/CT) in the assessment of low back pain in elderly patients with degenerative lumbar spine disease, underlining the clinical utility of bone SPECT/CT imaging in this clinical population to inform diagnosis and treatment. Methods Between January 2016 and December 2017, we used bone SPECT/CT to successfully identify the cause of low back pain in five elderly patients. All patients had been scheduled for extensive spinal fusion surgery based on conventional imaging (plain radiography, computed tomography, and magnetic resonance). Results After diagnosis using bone SPECT/CT, three patients underwent spinal fusion at 1–2 levels with specific degenerative disk and joint disease, with the other two patients successfully treated using a conservative approach for a non-traumatic insufficiency fracture of the endplate of the L4 vertebral body and a fracture of the transverse process of L3. Clinically meaningful decrease in pain and fracture healing were obtained with conservative treatment. Conclusion Bone SPECT/CT was useful to identify the specific cause of pain in elderly patients with lumbar degenerative disease and to provide appropriate treatment, avoiding the unnecessary use of invasive spinal fusion surgery. Therefore, the clinical utility of bone SPECT/CT is potentially high as it improves diagnosis and lowers the risk of inappropriate invasive spinal surgery.

Abstract Background Detecting culprit coronary arteries in patients with ischemia using only myocardial perfusion single-photon emission computed tomography (SPECT) can be challenging. This study aimed to improve the detection of culprit regions using an artificial neural network (ANN) to analyze hybrid images of coronary computed tomography angiography (CCTA) and myocardial perfusion SPECT. Methods This study enrolled 59 patients with stable coronary artery disease (CAD) who had been assessed by coronary angiography within 60 days of myocardial perfusion SPECT. Two nuclear medicine physicians interpreted the myocardial perfusion SPECT and hybrid images with four grades of confidence, then drew regions on polar maps to identify culprit coronary arteries. The gold standard was determined by the consensus of two other nuclear cardiology specialist based on coronary angiography findings and clinical information. The ability to detect culprit coronary arteries was compared among experienced nuclear cardiologists and the ANN. Receiver operating characteristics (ROC) curves were analyzed and areas under the ROC curves (AUC) were determined. Results Using hybrid images, observer A detected CAD in the right (RCA), left anterior descending (LAD), and left circumflex (LCX) coronary arteries with 83.6%, 89.3%, and 94.4% accuracy, respectively and observer B did so with 72.9%, 84.2%, and 89.3%, respectively. The ANN was 79.1%, 89.8%, and 89.3% accurate for each coronary artery. Diagnostic accuracy was comparable between the ANN and experienced nuclear medicine physicians. The AUC was significantly improved using hybrid images in the RCA region (observer A: from 0.715 to 0.835, p = 0.0031; observer B: from 0.771 to 0.843, p = 0.042). To detect culprit coronary arteries in perfusion defects of the inferior wall without using hybrid images was problematic because the perfused areas of the LCX and RCA varied among individuals. Conclusions Hybrid images of CCTA and myocardial perfusion SPECT are useful for detecting culprit coronary arteries. Diagnoses using artificial intelligence are comparable to that by nuclear medicine physicians.

Abstract Introduction The incidence of prostate cancer in Japan continues to increase, necessitating the continued development of effective therapies and strategies. Recent advances in treatments have improved the prognosis of metastatic disease and highlighted the importance of treating bone metastases to reduce the incidence of skeletal complications and improve patients’ quality of life. With the increasing number of treatment options that have become available, including bone-targeted therapy with the alpha emitter radium-223 dichloride (Ra-223), Japanese clinicians are faced with making difficult decisions on the choice of optimal treatment strategy. In such situations, guidance based on expert opinions can be beneficial. Methods A panel meeting of 27 Japanese experts in the management of prostate cancer was held to share opinions and to establish consensus recommendations on key clinical questions. Panelists were asked to vote on more than 40 questions pertinent to prostate cancer, and the answers helped guide a comprehensive discussion. Results The panel reached a consensus on key topics related to the optimal treatment strategy for Ra-223 therapy, namely, that patients with symptomatic, metastatic castration-resistant prostate cancer (CRPC) would benefit most from the use of this agent and that this treatment therapy should be provided before chemotherapy. Other topics that achieved consensus included: monitoring for osteoporosis and providing treatment if necessary during androgen deprivation therapy; performing magnetic resonance imaging in the presence of discrepancies in bone scintigram and computed tomography scans; monitoring alkaline phosphatase during CRPC treatment; using osteoclast-targeting in patients with CRPC with bone metastases; and using osteoclast-targeted agents combined with Ra-223. Conclusion These consensus recommendations and the updated information which became available subsequent to the panel meeting included here provide useful information for clinicians to aid in designing optimal treatment strategies for their patients. Funding Bayer Yakuhin Ltd.

Background Electromyography (EMG) has been used for evaluating skeletal muscle activity during pitching. However, it is difficult to observe the influence of movement on skeletal muscle activity in deep-lying regions of the trunk and extremities using EMG. An alternative method that may be used is the measurement of glucose metabolism of skeletal muscle using positron emission tomography-computed tomography (PET-CT). This technique is a reliable measure of muscle metabolism, demonstrating a high correlation with the intensity of muscle activity. This study aimed to evaluate whole-body skeletal muscle metabolism during pitching using PET-CT. Methods Ten uninjured, skilled, adult pitchers, who were active at college or professional level, threw 40 baseballs at maximal effort before an intravenous injection of 37 MBq of 18F-fluorodeoxyglucose (FDG). Subsequently, additional 40 balls were pitched. PET-CT images were obtained 50 min after FDG injection, and regions of interest were defined within 72 muscles. The standardized uptake value (SUV) of FDG by muscle tissue per unit volume was calculated, and the mean SUV of the pitchers was compared with that of a healthy adult control group who did not exercise before the measurements. Statistical analysis was performed using a t-test, and P

Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart.

Background: Sports injury prevention training programs have been reported to be effective in decreasing the incidence of injuries. The aim of this study was to evaluate the effects of a 6-month training period, using part 2 of the FIFA11+ program (the Fédération Internationale de Football), on the activation and strength of core and lower limb muscles and on static and dynamic balance performance. Study Design: Case series; level of evidence, 4. Methods: Eight college male soccer players, aged mean 20.4 ± 0.5 years old, completed the FIFA11+ program at least three times per week for 6 months. The following variables were measured both before and after the 6-month training program: activities of more than 30 muscles (core and lower limb muscles), measured using the standardized uptake values of 18F-fluorodeoxyglucose on positron emission tomography; isokinetic strength of the knee flexor and extensor and hip abductor muscles, measured at 60° s −1 ; static balance over a 60-s period, measured using a gravicorder; and dynamic balance, measured using the star excursion balance test. Results: Training improved the activity levels of core (obliquus externus abdominis and erector spinae) and lower limb (tibialis anterior) muscles ( p ≤ 0.03), corrected the between-limb difference in the activation of the semimembranosus and improved dynamic balance, with a greater training effect on the nondominant limb ( p ≤ 0.02). Training also improved the knee flexor force of the nondominant lower limb ( p = 0.02). Conclusion: Routine performance of the FIFA11+ program can improve the activation of core and lower limb muscles, with a concomitant improvement in dynamic balance. These improvements could be beneficial in lowering the risk of sports-related injuries.

Objective(s): High-risk neuroblastoma is a childhood cancer with poorprognosis despite modern multimodality therapy. Internal radiotherapy using131I-metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it isresistant to chemotherapy. The aim of this study is to evaluate the safety and efficacyof 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapyand hematopoietic stem cell transplantation.Methods: Patients with high-risk neuroblastoma will be enrolled in this study. A totalof 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG andafter safety evaluation will undergo high-dose chemotherapy and hematopoietic stemcell transplantation. Autologous and allogeneic stem cell sources will be accepted.After engraftment or 28 days after hematopoietic stem cell transplantation, the safetyand response will be evaluated.Conclusion: This is the first prospective study of 131I-MIBG with high-dosechemotherapy and hematopoietic stem cell transplantation in Japan. The results willbe the basis of a future nationwide clinical trial.

We recently developed 125I- and 211At-labeled monomer RGD peptides using a novel radiolabeling method. Both labeled peptides showed high accumulation in the tumor and exhibited similar biodistribution, demonstrating their usefulness for radiotheranostics. This study applied the labeling method to a dimer RGD peptide with the aim of gaining higher accumulation in tumor tissues based on improved affinity with αvβ3 integrin. We synthesized an iodine-introduced dimer RGD peptide, E[c(RGDfK)] (6), and an 125/131I-labeled dimer RGD peptide, E[c(RGDfK)]{[125/131I]c[RGDf(4-I)K]} ([125/131I]6), and evaluated them as a preliminary step to the synthesis of an 211At-labeled dimer RGD peptide. The affinity of 6 for αvβ3 integrin was higher than that of a monomer RGD peptide. In the biodistribution experiment at 4 h postinjection, the accumulation of [125I]6 (4.12 ± 0.42% ID/g) in the tumor was significantly increased compared with that of 125I-labeled monomer RGD peptide (2.93 ± 0.08% ID/g). Moreover, the accumulation of [125I]6 in the tumor was greatly inhibited by co-injection of an excess RGD peptide. However, a single injection of [131I]6 (11.1 MBq) did not inhibit tumor growth in tumor-bearing mice. We expect that the labeling method for targeted alpha therapy with 211At using a dimer RGD peptide could prove useful in future clinical applications.

Abstract Background Pheochromocytomas are rare neuroendocrine tumors, with a malignancy frequency of approximately 10%. The treatment of malignant pheochromocytoma is palliative, and the traditional management strategy has limited efficacy. Furthermore, no clear criteria exist for the treatment of metastatic pheochromocytoma, especially for unresectable lesions. We report a case of complete remission of metastatic pheochromocytoma in 123I-metaiodobenzylguanidine (MIBG) scintigraphy after a single session of 131I-MIBG therapy. Case presentation A 61-year-old woman had a right adrenal grand tumor and lymph node metastasis on the hilum of the right kidney, both of which incorporated MIBG. After surgery, immunostaining of a tumor specimen showed expression of the tumor makers chromogranin and synaptophysin. One year postoperatively, abdominal computed tomography revealed a local recurrence and retroperitoneal lymph node swelling. The local recurrence was positive for MIBG uptake, whereas the swollen retroperitoneal lymph nodes were negative. She underwent surgery again, but the local recurrence was unresectable because of rigid adhesion to the surrounding tissue. Immunostaining of an intraoperatively extracted swollen retroperitoneal lymph node showed expression of tumor markers. The patient then underwent a single session of 131I-MIBG therapy (7.4 GBq, 200 mCi), after which the residual lesions no longer incorporated MIBG, and a complete response in 123I- metaiodobenzylguanidine (MIBG) scintigraphy was achieved. The 131I-MIBG treatment was repeated 6 months later. None of the lesions were positive for MIBG uptake. Conclusions 131I-MIBG therapy efficaciously treats unresectable lesions that are positive for MIBG uptake.

Abstract Idiopathic olfactory disorder is resistant to treatment, and the recovery time is long. This study investigated the prognostic value of the migration of nasally administered thallium-201 to the olfactory bulb (thallium migration to the OB), a measure of olfactory nerve damage, in patients with idiopathic olfactory disorders. Twenty-four patients with idiopathic olfactory disorders were enrolled in the study (7 women and 17 men; aged 23–73 years). We retrospectively analyzed potential prognostic markers in subjects who underwent thallium-based olfactory imaging with the nasal administration of thallium-201 before conventional treatment with the Japanese herbal medicine tokishakuyakusan and compared those data with the prognosis. Log-rank tests were performed to assess the relationship between thallium migration to the OB (

Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC50 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

The purpose of this study is to develop peptide-based platelet-derived growth factor receptor β (PDGFRβ) imaging probes and examine the effects of several linkers, namely un-natural amino acids (D-alanine and β-alanine) and ethylene-glycol (EG), on the properties of Ga-DOTA-(linker)-IPLPPPRRPFFK peptides. Seven radiotracers, 67Ga-DOTA-(linker)-IPLPPPRRPFFK peptides, were designed, synthesized, and evaluated. The stability and cell uptake in PDGFRβ positive peptide cells were evaluated in vitro. The biodistribution of [67Ga]Ga-DOTA-EG2-IPLPPPRRPFFK ([67Ga]27) and [67Ga]Ga-DOTA-EG4-IPLPPPRRPFFK ([67Ga]28), which were selected based on in vitro stability in murine plasma and cell uptake rates, were determined in BxPC3-luc-bearing nu/nu mice. Seven 67Ga-labeled peptides were successfully synthesized with high radiochemical yields (>85%) and purities (>99%). All evaluated radiotracers were stable in PBS (pH 7.4) at 37 °C. However, only [67Ga]27 and [67Ga]28 remained more than 75% after incubation in murine plasma at 37 °C for 1 h. [67Ga]27 exhibited the highest BxPC3-luc cell uptake among the prepared radiolabeled peptides. As regards the results of the biodistribution experiments, the tumor-to-blood ratios of [67Ga]27 and [67Ga]28 at 1 h post-injection were 2.61 ± 0.75 and 2.05 ± 0.77, respectively. Co-injection of [67Ga]27 and an excess amount of IPLPPPRRPFFK peptide as a blocking agent can significantly decrease this ratio. However, tumor accumulation was not considered sufficient. Therefore, further probe modification is required to assess tumor accumulation for in vivo imaging.

123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy is used for evaluating disease extent in children with neuroblastoma. 131I-mIBG therapy has been used for evaluation in children with high-risk neuroblastoma, and post-therapy 131I-mIBG scintigraphy may detect more lesions compared with diagnostic 123I-mIBG scintigraphy. However, no studies have yet revealed the detection rate of hidden mIBG-avid lesions on post-therapy 131I-mIBG whole-body scan (WBS) and SPECT images in neuroblastoma children without mIBG-avid lesions as demonstrated by diagnostic 123I-mIBG scintigraphy. We retrospectively examined the diagnostic utility of post-therapy 131I-mIBG scintigraphy in children who received 131I-mIBG as consolidation therapy. Nineteen children with complete response to primary therapy were examined. Post-therapy 131I-mIBG scintigraphy was performed four days after injection. The post-therapy 131I-mIBG scintigraphy, 4 children exhibited abnormal uptake on the WBS. Post-therapy 131I-mIBG SPECT/CT provided additional information in 2 cases. In total, 6 children exhibited abnormal uptake. The site of abnormal accumulation was on the recurrence site in one case, operation sites in five cases, and bone metastasis in one case. Post-therapy 131I-mIBG scintigraphy could detect residual disease that was not recognized using diagnostic 123I-mIBG scintigraphy in 32% of children with high-risk neuroblastoma and ganglioneuroblastoma. The diagnostic use of post-therapy 131I-mIBG scintigraphy can provide valuable information for detecting residual disease.

Rociletinib (CO-1686), a 2,4-diaminopyrimidine derivative, is a highly potent tyrosine kinase inhibitor (TKI) that acts on epidermal growth factor receptor (EGFR) with L858R/T790M mutations. We supposed radioiodinated CO-1686 would function as a useful tool for monitoring EGFR L858R/T790M mutations. To aid in patient selection before therapy with EGFR-TKIs, this study aimed to develop a 125I-labeled derivative of CO-1686, N-{3-[(2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-4-yl] amino}-5-([125I]iodophenyl)acrylamide ([125I]ICO1686) and evaluate its selectivity toward EGFR L858R/T790M. Radiosynthesis was performed by iododestannylation of the corresponding tributylstannyl precursor with [125I]NaI and N-chlorosuccinimide. The selectivity of the tracer for detecting EGFR L858R/T790M was evaluated using three relevant non-small cell lung cancer (NSCLC) cell lines—H1975, H3255 and H441 overexpressing the dual mutation EGFR L858R/T790M, active mutant EGFR L858R and wild-type EGFR, respectively. The nonradioactive ICO1686 and the precursor compound were successfully synthesized. A novel radiolabeled probe, [125I]ICO1686, was prepared with high radiochemical yield (77%) and purity (>99%). ICO1686 exhibited high cytotoxicity toward H1975 (IC50 0.20 ± 0.05 μM) and H3255 (IC50 0.50 ± 0.21 μM), which is comparable to that of CO-1686. In contrast, the cytotoxicity of ICO1686 toward H441 was 10-fold lower than that toward H1975. In the cell uptake study, the radioactivity uptake of [125I]ICO1686 in H1975 was 101.52% dose/mg, whereas the uptakes in H3255 and H441 were 33.52 and 8.95% dose/mg, respectively. The uptake of [125I]ICO1686 in H1975 was greatly reduced to 45.61% dose/mg protein by treatment with excess CO-1686. In vivo biodistribution study of the radiotracer found that its accumulation in H1975 tumor (1.77 ± 0.43% ID/g) was comparable to that in H3255 tumor (1.63 ± 0.23% ID/g) and the accumulation in H1975 tumor was not reduced by pretreatment with an excess dose of CO-1686. Although this radiotracer exhibited highly specific in vitro uptake in target cancer cells, structural modification is required to improve in vivo biodistribution.

Objective(s): We investigated a frequency of lower extremity uptake on the radioactive iodine (RAI) whole body scan (WBS) after RAI treatment in patients with differentiated thyroid cancer, in order to retrospectively examine whether or not the frequency was pathological. Methods: This retrospective study included 170 patients with thyroid cancer, undergoing RAI treatment. Overall, 99r (58%) and 71 (42%)patients received single and multiple RAI treatments, respectively. Post-therapeutic WBS was acquired after 3 days of RAI administration. For patients with multiple RAI treatments, the WBS of their last RAI treatment was evaluated. Lower extremity uptake on post-therapeutic WBS was classified into 3 categories: bilateral femoral uptake (type A), bilateral femoral and tibia uptake (type B), and uptake in bilateral upper and lower extremities (type C). Then, the patients with RAI uptake in the lower extremities on WBS were analyzed with clinical parameters. Results: Overall, 99 patients (58%) had the extremity uptake on their posttherapeutic RAI WBS. As the results indicated, 42 ,53, and 4 patients had type A, type B, and type C uptakes, respectively. Lower extremity uptake was significantly associated with younger age, not only in subjects with multiple RAI treatments but also in all the patients (P

BACKGROUND:Exercise is one of the few treatments that provide significant improvements in chronic low back pain (CLBP). We developed an innovative exercise device for abdominal trunk muscles. This device can be used in a sitting or standing position and contains a built-in system to measure abdominal trunk muscle strength. We examined whether subjects can adequately use the device to perform the exercises and measure their abdominal trunk muscle strength. METHODS:We collected data on the body height, body weight, body mass index, and girth of 30 healthy male volunteers, and measured their grip power and trunk extensor muscle strength using a dynamometer. The volunteers performed a sit-up test as an indicator of trunk flexor muscle strength, and we measured their abdominal muscle strength using the device. We then evaluated the correlations between abdominal trunk muscle strength and anthropometric parameters as well as the strength of other muscles. In subsequent tests, 5 of the 30 subjects participated in two positron emission tomography (PET) series consisting of examinations after a resting period (control study) and during exercise (exercise study). For the exercise study, the subjects performed 2 sets of exercises for 20 minutes using the device before and after an injection of 18F-fluorodeoxyglucose (FDG). PET-computed tomography images were obtained 60 minutes after FDG injection in each study. We compared the skeletal muscle metabolism of the participants in both studies using the standardized uptake value. RESULTS:The muscle strength measured by the device and the 30-second sit-up frequency were correlated. FDG accumulation within the diaphragm and abdominal rectus muscles was significantly higher in the exercise study. CONCLUSION:Our innovative exercise device facilitates a coordinated contraction of the abdominal trunk muscles at the anterior aspect and the roof of the core, and enables subjects to measure the strength of these muscles.

Mitochondria play an important role in energy production for the cell. The proper function of a myocardial cell largely depends on the functional capacity of the mitochondria. Therefore it is necessary to establish a novel and reliable method for a non-invasive assessment of mitochondrial function and metabolism in humans. Although originally designed for evaluating myocardial perfusion, 99mTc-MIBI can be also used to evaluate cardiac mitochondrial function. In a clinical study on ischemic heart disease, reverse redistribution of 99mTc-MIBI was evident after direct percutaneous transluminal coronary angioplasty. The presence of increased washout of 99mTc-MIBI was associated with the infarct-related artery and preserved left ventricular function. In non-ischemic cardiomyopathy, an increased washout rate of 99mTc-MIBI, which correlated inversely with left ventricular ejection fraction, was observed in patients with congestive heart failure. Increased 99mTc-MIBI washout was also observed in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and in doxorubicin-induced cardiomyopathy. Noninvasive assessment of cardiac mitochondrial function could be greatly beneficial in monitoring possible cardiotoxic drug use and in the evaluation of cardiac damage in clinical medicine.

Objective: The current study aimed to determine the efficacy of radioiodine-131 (131I) ablation therapy with thyroid hormone replacement one day before 131I administration in patients with well-differentiated thyroid cancer (DTC). Methods: This retrospective study included 29 patients who underwent 131I therapies twice for DTC during 6-12 months. Since all the patients obviously had residual lesions by their serum thymoglobulin levels or their scintigrams at the first therapies, they underwent the second 131I therapies without diagnostic scintigraphy after the first therapies. After confirming the sufficient elevation of TSH concentration, thyroid hormone replacement was resumed one day before 131I administration (3.7-7.4GBq). The ablation rate of thyroid remnant at the first 131I therapy was evaluated by comparing 131I post-therapeutic images of the two treatments. Results: Three patients were administrated thyroid hormone after 131I therapy because of insufficient TSH concentration under thyroid hormone withdrawal. In the remaining 26 patients, 41 thyroid remnant accumulations were detected in all 26 patients at the first 131I therapy. Based on the second 131I post-therapeutic images, successful ablation was confirmed in 24 of 26 patients (92.3%) and 38 of 41 sites (92.7%), which was comparable with historically reported ablation rates. Conclusion: Thyroid hormone replacement one day before 131I therapy could provide a sufficiently high ablation rate in patients with DTC.

PURPOSE:To develop a superior VAChT imaging probe for SPECT, radiolabeled (-)-OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities. PROCEDURES:Radioiodinated o-iodo-trans-decalinvesamicol ([125I]OIDV) has a high binding affinity for vesicular acetylcholine transporter (VAChT) both in vitro and in vivo. Racemic [125I]OIDV was separated into its two optical isomers (-)-[125I]OIDV and (+)-[125I]OIDV by HPLC. To investigate VAChT binding affinity (Ki) of two OIDV isomers, in vitro binding assays were performed. In vivo biodistribution study of each [125I]OIDV isomer in blood, brain regions and major organs of rats was performed at 2,30 and 60 min post-injection. In vivo blocking study were performed to reveal the binding selectivity of two [125I]OIDV isomers to VAChT in vivo. Ex vivo autoradiography were performed to reveal the regional brain distribution of two [125I]OIDV isomers and (-)-[123I]OIDV for SPECT at 60 min postinjection. RESULTS:VAChT binding affinity (Ki) of (-)-[125I]OIDV and (+)-[125I]OIDV was 22.1 nM and 79.0 nM, respectively. At 2 min post-injection, accumulation of (-)-[125I]OIDV was the same as that of (+)-[125I]OIDV. However, (+)-[125I]OIDV clearance from the brain was faster than (-)-[125I]OIDV. At 30 min post-injection, accumulation of (-)-[125I]OIDV (0.62 ± 0.10%ID/g) was higher than (+)-[125I]OIDV (0.46 ± 0.07%ID/g) in the cortex. Inhibition of OIDV binding showed that (-)-[125I]OIDV was selectively accumulated in regions known to express VAChT in the rat brain, and ex vivo autoradiography further confirmed these results showing similar accumulation of (-)-[125I]OIDV in these regions. Furthermore, (-)-[123I]OIDV for SPECT showed the same regional brain distribution as (-)-[125I]OIDV. CONCLUSION:These results suggest that radioiodinated (-)-OIDV may be a potentially useful tool for studying presynaptic cholinergic neurons in the brain.

Neuroblastoma, which derives from neural crest, is the most common extracranial solid cancer in childhood. The tumors express the norepinephrine (NE) transporters on their cell membrane and take in metaiodobenzylguanidine (MIBG) via a NE transporter. Since iodine-131 (I-131) MIBG therapy was firstly reported, many trails of MIBG therapy in patients with neuroblastoma were performed. Though monotherapy with a low dose of I-131 MIBG could achieve high-probability pain reduction, the objective response was poor. In contrast, more than 12 mCi/kg I-131 MIBG administrations with or without hematopoietic cell transplantation (HCT) obtain relatively good responses in patients with refractory or relapsed neuroblastoma. The combination therapy with I-131 MIBG and other modalities such as nonmyeloablative chemotherapy and myeloablative chemotherapy with HCT improved the therapeutic response in patients with refractory or relapsed neuroblastoma. In addition, I-131 MIBG therapy incorporated in the induction therapy was proved to be feasible in patients with newly diagnosed neuroblastoma. To expand more the use of MIBG therapy for neuroblastoma, further studies will be needed especially in the use at an earlier stage from diagnosis, in the use with other radionuclide formations of MIBG, and in combined use with other therapeutic agents.

PURPOSE: This study investigated the effect of the FIFA 11+ warm-up program on whole body muscle activity using positron emission tomography. METHODS: Ten healthy male volunteers were divided into a control group and a group that performed injury prevention exercises (The 11+). The subjects of the control group were placed in a sitting position for 20 min and 37 MBq of (18)F-fluorodeoxyglucose (FDG) was injected intravenously. The subjects then remained seated for 45 min. The subjects of the exercise group performed part 2 of the 11+for 20 min, after which FDG was injected. They then performed part 2 of the 11+for 20 min, and rested for 25 min in a sitting position. Positron emission tomography-computed tomography images were obtained 50 min after FDG injection in each group. Regions of interest were defined within 30 muscles. The standardized uptake value was calculated to examine the FDG uptake of muscle tissue per unit volume. RESULTS: FDG accumulation within the abdominal rectus, gluteus medius and minimus were significantly higher in the exercise group than in the control group (P

PURPOSE: The aim of this study was to assess whether migration of thallium-201 ((201)Tl) to the olfactory bulb were reduced in patients with olfactory impairments in comparison to healthy volunteers after nasal administration of (201)Tl. PROCEDURES: 10 healthy volunteers and 21 patients enrolled in the study (19 males and 12 females; 26-71 years old). The causes of olfactory dysfunction in the patients were head trauma (n = 7), upper respiratory tract infection (n = 7), and chronic rhinosinusitis (n = 7). (201)TlCl was administered unilaterally to the olfactory cleft, and SPECT-CT was conducted 24 h later. Separate MRI images were merged with the SPECT images. (201)Tl olfactory migration was also correlated with the volume of the olfactory bulb determined from MRI images, as well as with odor recognition thresholds measured by using T&T olfactometry. RESULTS: Nasal (201)Tl migration to the olfactory bulb was significantly lower in the olfactory-impaired patients than in healthy volunteers. The migration of (201)Tl to the olfactory bulb was significantly correlated with odor recognition thresholds obtained with T&T olfactometry and correlated with the volume of the olfactory bulb determined from MRI images when all subjects were included. CONCLUSIONS: Assessment of the (201)Tl migration to the olfactory bulb was the new method for the evaluation of the olfactory nerve connectivity in patients with impaired olfaction.