125I-labeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (125I-OI5V) imaging visualized augmented sigma-1 receptor expression according to the severity of myocardial ischemia.

BACKGROUND: We aimed to explore how the severity of myocardial ischemia affects myocardial sigma-1 receptor (Sig-1R) expression using 125I-labeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (125I-OI5V) imaging. METHODS AND RESULTS: The left coronary artery was occluded for 30, 20, and 10 minute, to vary the severity of myocardial ischemia, followed by reperfusion. Dual-tracer autoradiography of the left ventricular short-axis slices was performed 3 and 7 days after reperfusion. 125I-OI5V was injected 30 minute before sacrifice and the area at risk (AAR) was evaluated by 99mTc-MIBI. Intense 125I-OI5V uptake was observed in the AAR and was significantly increased with increasing ischemia duration. To evaluate salvaged and nonsalvaged areas (preserved and decreased perfusion areas), triple-tracer autoradiography was performed 3 days after reperfusion. After dual-tracer autoradiography, 201Tl was injected 20 minute post 125I-OI5V injection. On triple-tracer autoradiography, the AAR/normally perfused area 125I-OI5V uptake ratio was positively correlated with the nonsalvaged area/whole left ventricular (LV) area ratio (P < .05). The AAR/normally perfused area 125I-OI5V uptake ratio was negatively correlated with the 201Tl uptake ratio of the AAR to normally perfused areas (P < .05). The comparison of the immunostaining distribution of 125I-OI5V and the macrophage marker CD68 revealed that 125I-OI5V was present mainly in, and immediately adjacent to the macrophage infiltration area. CONCLUSIONS: Significant 125I-OI5V uptake in the AAR depends on the duration of ischemia and reduced 201Tl uptake; furthermore, 125I-OI5V was found in and around the macrophage infiltrate area. These results indicate that iodine-labeled OI5V is a promising tool for visualizing Sig-1R expression according to the ischemic burden.

Long-term outcomes and prognostic factors of patients with lung metastases from differentiated thyroid cancer after radioiodine therapy in Japan.

Long-term survival in patients with differentiated thyroid cancer (DTC) and lung metastasis remains unexplored in Japan. This study aimed to investigate the long-term survival and prognostic factors of radioiodine therapy (RIT) in a University Hospital setting. This retrospective study included 62 patients with lung metastases from DTC who received RIT between March 2005 and December 2016. According to the 131I whole-body scan and chest computed tomography results, lung metastases were classified as 131I-avid or non-131I-avid, and miliary, micronodular, or macronodular metastases. The 5- and 10-year overall survival (OS) rates from the initial RIT were calculated by the Kaplan-Meier method, and a proportional hazard fit analysis was performed to determine prognostic factors. With a median follow-up of 7.9 years, the 5- and 10-year OS rates from the initial RIT were 93% and 72%, respectively. Univariable and multivariable analyses of patient subgroups revealed that macronodular lung metastases (defined as nodules >1 cm), older age at initial RIT, and high thyroglobulin values (>400 ng/mL) at initial RIT predicted low OS. The 5- and 10-year OS rates of DTC patients with lung metastases were similar to those in previous Japanese reports, which included a smaller sample size compared with ours. Patients with ≤1 cm lung metastases, aged ≤55 years, and a thyroglobulin level of ≤400 ng/mL at the initial RIT had favorable outcomes.

Visualization of Dynamic Expression of Myocardial Sigma-1 Receptor After Myocardial Ischemia and Reperfusion Using Radioiodine-Labeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) Imaging.

BACKGROUND: This study chronologically evaluated the expression of the intensity and distribution of the sigma-1 receptor (σ1R) demonstrated by radiolabeled 2-[4-(2-iodophenyl)piperidino]cyclopentanol (OI5V) in a rat model of myocardial ischemia and reperfusion.Methods and Results:The left coronary artery was occluded for 30 min, followed by reperfusion. Dual-tracer autoradiography with 125I-OI5V and 99 mTc-MIBI was performed to assess the spatiotemporal changes in 125I-OI5V uptake (n=5-6). Significant and peaked 125I-OI5V uptake in the ischemic area was observed at 3 days after reperfusion, and the 125I-OI5V uptake ratio of ischemic area to normally perfused left ventricular area decreased gradually from 3 to 28 days (mean value±SD; 0.90±0.12 at 1 day, 1.89±0.19 at 3 days, 1.52±0.17 at 7 days, 1.34±0.13 at 14 days, and 1.16±0.14 at 28 days, respectively). Triple-tracer autoradiography with 125I-OI5V, 99 mTc-MIBI, and 201TlCl was performed to evaluate 125I-OI5V uptake in the ischemic area in relation to the residual perfusion at 7 days (n=4). The 125I-OI5V uptake ratio of the non-salvaged area was higher compared to that of the salvaged area in the ischemic area. 123I-OI5V and 99 mTc-MIBI SPECT/CT was performed 3 days after reperfusion (n=3), and the in vivo images showed clear uptake of 123I-OI5V in the perfusion defect area. CONCLUSIONS: The present study confirmed the spatiotemporal expression pattern of σ1R expression. Non-invasive σ1R imaging with 123I or 125I-OI5V was feasible to monitor the expression of σ1R after myocardial ischemia and reperfusion.

Radiation exposure lymphocyte damage assessed by γ-H2AX level using flow cytometry.

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 (Sblood←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.

Evaluating the diagnostic efficacy of whole-body MRI versus 123I-mIBG/131I-mIBG imaging in metastatic pheochromocytoma and paraganglioma.

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.

Recent Advances in Radiopharmaceutical Theranostics of Pheochromocytoma and Paraganglioma.

As a rare kind of non-epithelial neuroendocrine neoplasms, paragangliomas (PGLs) exhibit various clinical characteristics with excessive catecholamine secretion and have been a research focus in recent years. Although several modalities are available nowadays, radiopharmaceuticals play an integral role in the management of PGLs. Theranostics utilises radiopharmaceuticals for diagnostic and therapeutic intentions by aiming at a specific target in tumour and has been considered a possible means in diagnosis, staging, monitoring and treatment planning. Numerous radiopharmaceuticals have been developed over the past decades. 123/131-Metaiodobenzylguanidine (123/131I-MIBG), the theranostics pair target on norepinephrine transporter system, has remained a fantastic protocol for patients with PGLs because of disease control with limited toxicity. The high-specific-activity 131I-MIBG was authorised by the Food and Drug Administration as a systemic treatment method for metastatic PGLs in 2018. Afterward, peptide receptor radionuclide therapy, which uses radiolabelled somatostatin (SST) analogues, has been exploited as a superior substitute. 68Ga-somatostatin analogue (SSA) PET showed significant performance in diagnosing PGLs than MIBG scintigraphy, especially in patients with head and neck PGLs or SDHx mutation. 90Y/177Lu-DOTA-SSA is highly successful and has preserved favourable safety with mounting evidence regarding objective response, disease stabilisation, symptomatic and hormonal management and quality of life preservation. Besides the ordinary beta emitters, alpha-emitters such as 211At-MABG and 225Ac-DOTATATE have been investigated intensively in recent years. However, many studies are still in the pre-clinical stage, and more research is necessary. This review summarises the developments and recent advances in radiopharmaceutical theranostics of PGLs.

Development of a novel small-animal myocardial phantom can evaluate the image quality of dual-isotope simultaneous acquisition (DISA).

BACKGROUND: Myocardial phantom studies are widely used as a tool to accurately assess the physical phenomenon of dual-isotope simultaneous acquisition (DISA) in the small-animal fields. However, the previous phantom did not reproduce the structures of rats or mice. The aim of this study was to develop a novel myocardial phantom simulating the structure of a small animal that can be evaluated using the image quality of DISA. METHODS: A novel small-animal myocardial phantom that simulated a rat was constructed by the myocardium, liver, lung, spine, and torso. Normal and inferior wall defect myocardial phantoms were filled with 99mTc or 18F solution to simulate single-isotope acquisition (SIA) and DISA. Phantom and small-animal images with no scatter correction (nonSC) and scatter correction (SC) were created. RESULTS: The 99mTc DISA with SC showed a low %CV compared to that with nonSC. Although the 99mTc DISA with nonSC had lower cavity contrast than that of 99mTc SIA with nonSC, the cavity contrast of SC had similar values between SIA and DISA. The minimum %uptake of 99mTc SIA with nonSC was a lower value compared to that of 99mTc DISA with nonSC. The 99mTc DISA was equivalent to the minimum %uptake of 99mTc SIA by SC. CONCLUSION: We have developed a novel myocardial phantom for the rat model to evaluate the image quality for reproducing the physical phenomenon associated with radiation attenuation and scattering. Furthermore, we could demonstrate the usefulness of the novel small-animal myocardial phantom by image quality evaluation of DISA with 99mTc and 18F compared to SIA.

Prognostic factors for refractory pheochromocytoma and paraganglioma after 131I-metaiodobenzylguanidine therapy.

OBJECTIVE: Given the rarity of refractory pheochromocytoma and paraganglioma (PPGL), outcomes and prognostic factors after 131I-metaiodobenzylguanidine (131I-mIBG) treatment still remain unclear. Therefore, this study evaluated whether baseline characteristics at initial 131I-mIBG therapy and imaging response to repeated 131I-mIBG therapy could be prognostic factors for refractory PPGL. METHODS: All patients [n = 59 (male/female = 35/24), median age; 49.3 years] with refractory PPGL who received 131I-mIBG therapy at our institution between September 2009 and September 2019 were retrospectively reviewed for the effects of the following factors on overall survival: age, sex, hypertension, diabetes mellitus, palpitations, constipation, cancer pain, catecholamines values, past history of therapy (external beam radiation for bone metastasis, operation, and chemotherapy), metastasis sites, and response to 131I-mIBG treatments. RESULTS: Throughout the follow-up period, 18 patients died from disease exacerbation. The estimated 5- and 10-year survival rates were 79.4% and 67.2% from the initial diagnoses of refractory PPGL and 68.5% and 49.9% from the first 131I-mIBG therapy, respectively. The multivariate Cox proportional hazards model showed that progressive disease (PD) [hazard ratio (HR) 96.3, P = 0.011] and constipation (HR 8.2, P = 0.024) were adverse prognostic factors for overall survival after initial 131I-mIBG therapy. The log-rank test demonstrated that PD in response to 131I-mIBG therapies (P < 0.0001) and constipation (P < 0.01) were correlated with poor survival rates. CONCLUSIONS: Response to repeated 131I-mIBG treatment can be a strong predictor of prognosis after initial 131I-mIBG therapy for refractory PPGL. Repeated 131I-mIBG therapy may be a good option for controlling refractory PPGL.

Feasibility of 125I-RGD uptake as a marker of angiogenesis after myocardial infarction.

OBJECTIVE: Angiogenesis is an important process facilitating the healing process after myocardial infarction. 125I-RGD imaging may be a promising candidate to image angiogenesis but may also detect inflammation. METHODS: Left coronary artery was occluded for 30 min, followed by reperfusion in a rat model (n = 31). One, 3, 7 and 14 days, 1 and 2 months later, Triple-tracer autoradiography was performed. 125I-RGD (1.5 MBq) and 201Tl (15 MBq) were injected at 80 and 10 min before sacrifice. Left coronary artery was reoccluded and 99mTc-MIBI (150-180 MBq) was injected 1 min before sacrifice to verify the area at risk. Angiogenesis and macrophage infiltration were evaluated by immunohistochemical analysis with anti-alpha-smooth muscle actin and anti-CD68, respectively. RESULTS: 125I-RGD uptake ratio in the area at risk was weak at day 3 (1.23 ± 0.23 but increased markedly and peaked at day 7 (2.27 ± 0.37) followed by a gradual reduction until 1 and 2 months later (1.93 ± 0.16 at 1 month, 1.58 ± 0.15 at 2 month). In the immunohistochemical analysis, copious staining of anti-CD68 cells was observed, with anti-SMA cells stained only minimally at day 3. The number of anti-CD68 cells was decreased significantly at day 7 but largely absent at 1 month. Anti-SMA positive cells peaked at day 7 and reduced gradually until 1 month. CONCLUSIONS: Myocardial 125I-RGD uptake reflects angiogenesis rather than inflammation after myocardial infarction.

An open-label, single-arm, multi-center, phase II clinical trial of single-dose [131I]meta-iodobenzylguanidine therapy for patients with refractory pheochromocytoma and paraganglioma.

OBJECTIVE: In this phase II study, we aimed to investigate the efficacy and safety of single-dose [131I]meta-iodobenzylguanidine (131I-mIBG) therapy in patients with refractory pheochromocytoma and paraganglioma (PPGL). PATIENTS AND METHODS: This study was designed as an open-label, single-arm, multi-center, phase II clinical trial. The enrolled patients were administered 7.4 GBq of 131I-mIBG. Its efficacy was evaluated 12 and 24 weeks later, and its safety was monitored continuously until the end of the study. We evaluated the biochemical response rate as the primary endpoint using the one-sided exact binomial test based on the null hypothesis (≤ 5%). RESULTS: Seventeen patients were enrolled in this study, of which 16 were treated. The biochemical response rate (≥ 50% decrease in urinary catecholamines) was 23.5% (90% confidence interval: 8.5-46.1%, p = 0.009). The radiographic response rates, determined with CT/MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1 and 123I-mIBG scintigraphy were 5.9% (0.3%-25.0%) and 29.4% (12.4%-52.2%), respectively. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) were gastrointestinal symptoms including nausea, appetite loss, and constipation, which were, together, observed in 15 of 16 patients. Hematologic TEAEs up to grade 3 were observed in 14 of 16 patients. No grade 4 or higher TEAEs were observed. All patients had experienced at least one TEAE, but no fatal or irreversible TEAEs were observed. CONCLUSION: A single dose 131I-mIBG therapy was well tolerated by patients with PPGL, and statistically significantly reduced catecholamine levels compared to the threshold response rate, which may lead to an improved prognosis for these patients.

Colchicine treatment early after infarction attenuates myocardial inflammatory response demonstrated by 14C-methionine imaging and subsequent ventricular remodeling by quantitative gated SPECT.

OBJECTIVE: Colchicine has been used as an anti-inflammatory agent and may be cardioprotective after acute myocardial infarction (AMI). We investigated how colchicine administration after AMI affects the myocardial inflammatory response using 14C-methionine and subsequent ventricular remodeling using single-photon emission computed tomography (SPECT) in a rat model of AMI. METHODS: The left coronary artery (LCA) was occluded for 30 min followed by reperfusion. 14C-methionine was injected at 20 min before sacrifice. The LCA was re-occluded at 1 min before sacrifice and 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) was injected. Colchicine was administered intraperitoneally from day 1 to the day before 14C-methionine injection. Dual-tracer autoradiography of the left ventricular short-axis slices was performed. The methionine uptake ratio in an ischemic area was calculated. 99mTc-MIBI gated SPECT assessed end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF). On Cluster of Differentiation 68 with 4',6-diamidino-2-phenylindole (CD68/DAPI) staining the positive myocardial cell percentage in an ischemic area was calculated. RESULTS: In control rats, 14C-methionine uptake ratios on day 3 and 7 were 1.87 ± 0.15 and 1.39 ± 0.12, respectively. With colchicine, the uptake was reduced on days 3 (1.56 ± 0.26, p = 0.042) and 7 (1.23 ± 0.10, p = 0.030). Colchicine treated rats showed smaller EDV, ESV, and higher LVEF compared with control rats. At 8 weeks, those in control rats were 864 ± 115 µL, 620 ± 100 µL, 28.4 ± 2.5%, and in colchicine rats 665 ± 75 µL, 390 ± 97 µL, 42.2 ± 8.5% (p = 0.012, 0.0061, 0.0083), respectively. In control rats, CD68/DAPI positive myocardial cell percentages on days 3 and 7 were 38.4 ± 1.9% and 24.0 ± 2.4%, respectively. With colchicine, the percentages were reduced significantly on both days 3 (31.5 ± 2.0%, p < 0.0001) and 7 (12.0 ± 1.6%, p < 0.0001) as compared with the control. CONCLUSIONS: Short-term colchicine treatment after AMI attenuated the post-AMI inflammatory response and subsequent ventricular remodeling and dysfunction. 14C-methionine imaging and gated 99mTc-MIBI SPECT would be feasible to monitor the effectiveness of anti-inflammatory therapy and left ventricular function.

Serial examination of cardiac function and perfusion in growing rats using SPECT/CT for small animals.

Few studies have evaluated myocardial perfusion and ventricular function in normal, growing rats. We, therefore, evaluated serial changes in cardiac perfusion and function during the growth of normal rats using single photon emission computed tomography (SPECT) with technetium (99mTc)-sestamibi. Gated SPECT was serially performed in six normal rats. The left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF) were calculated with Quantitative Gated SPECT software. The perfusion distribution was calculated as the percentage uptake of each of the 17 segments using Quantitative Perfusion SPECT software. As expected, the body weight (BW) of the rats increased with growth, but their heart rates (HR) did not change over time. EF decreased very slowly over time and showed a negative correlation with BW. EDV, ESV and SV showed strong positive correlations with BW. There were no significant differences in the percentage segmental uptake in 13 of the 17 segments during growth, except for three basal and one apical segments. Therefore, a single normal database could be applied for the evaluation of perfusion abnormalities in rats of at least 8 to 28 weeks old.

Thallium-201 Imaging in Intact Olfactory Sensory Neurons with Reduced Pre-Synaptic Inhibition In Vivo.

In this study, we determined whether the 201Tl (thallium-201)-based olfactory imaging is affected if olfactory sensory neurons received reduced pre-synaptic inhibition signals from dopaminergic interneurons in the olfactory bulb in vivo. The thallium-201 migration rate to the olfactory bulb and the number of action potentials of olfactory sensory neurons were assessed 3 h following left side nasal administration of rotenone, a mitochondrial respiratory chain complex I inhibitor that decreases the number of dopaminergic interneurons without damaging the olfactory sensory neurons in the olfactory bulb, in mice (6-7 animals per group). The migration rate of thallium-201 to the olfactory bulb was significantly increased following intranasal administration of thallium-201 and rotenone (10 µg rotenone, p = 0.0012; 20 µg rotenone, p = 0.0012), compared with that in control mice. The number of action potentials was significantly reduced in the olfactory sensory neurons in the rotenone treated side of 20 µg rotenone-treated mice, compared with that in control mice (p = 0.0029). The migration rate of thallium-201 to the olfactory bulb assessed with SPECT-CT was significantly increased in rats 24 h after the left intranasal administration of thallium-201 and 100 µg rotenone, compared with that in control rats (p = 0.008, 5 rats per group). Our results suggest that thallium-201 migration to the olfactory bulb is increased in intact olfactory sensory neurons with reduced pre-synaptic inhibition from dopaminergic interneurons in olfactory bulb glomeruli.

Diagnostic Use of Post-therapy 131I-Meta-Iodobenzylguanidine Scintigraphy in Consolidation Therapy for Children with High-Risk Neuroblastoma.

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.

High-dose 131I-metaiodobenzylguanidine therapy in patients with high-risk neuroblastoma in Japan.

OBJECTIVE: The aim of the study was to investigate the outcomes and prognostic factors of high-dose 131I-metaiodobenzylguanidine (131I-MIBG) therapy in patients with refractory or relapsed neuroblastoma (NBL) in Japan. METHODS: We retrospectively analyzed 20 patients with refractory or relapsed high-risk NBL who underwent 131I-MIBG therapy with an administration dose ranging from 444 to 666 MBq/kg at Kanazawa University Hospital, Japan, between September 2008 and September 2013. We focused on measurements regarding their initial responses, prognostic factors, survivals, and toxicities following 131I-MIBG therapy using our hospital data and questionnaires from the hospitals that these patients were initially referred from. Furthermore, we performed Kaplan-Meier survival analysis to evaluate event-free survival (EFS) and overall survival (OS). RESULTS: In 19 patients with complete follow-up data, the median age at first 131I-MIBG treatment was 7.9 years (range 2.5-17.7 years). Following 131I-MIBG therapy, 17 of the 19 patients underwent stem-cell transplantations, and their treatment response was either complete (CR) or partial (PR) in three and two cases, respectively. The EFS and OS rates at 1 year following 131I-MIBG therapy were 42% and 58%, respectively, and those at 5 years following 131I-MIBG therapy were 16% and 42%, respectively. Using the two-sample log-rank test, the OS time following 131I-MIBG therapy was significantly longer for < 3-year time interval between the initial diagnosis and 131I-MIBG therapy (p = 0.017), Curie score < 16 just before 131I-MIBG therapy (p = 0.002), without pain (p = 0.002), without both vanillylmandelic acid (VMA) and homovanillic acid (HVA) elevation (p = 0.037) at 131I-MIBG therapy, and with CR or PR following 131I-MIBG therapy (p = 0.015). Although severe hematological toxicities were identified in all 19 patients, severe nonhematological toxicity was not recorded in any patient, except for one patient with grade 3 anorexia and nausea. CONCLUSIONS: High-dose 131I-MIBG therapy in patients with refractory or relapsed high-risk NBL can provide a favorable prognosis without severe nonhematological toxicities. Better prognosis may be anticipated in patients with the initial good response, no pain at 131I-MIBG therapy, no VMA and HVA elevation at 131I-MIBG therapy, low Curie score (< 16) just before 131I-MIBG therapy, and short time interval (< 3 years) between the initial diagnosis and 131I-MIBG therapy.

High-dose 131I-mIBG as consolidation therapy in pediatric patients with relapsed neuroblastoma and ganglioneuroblastoma: the Japanese experience.

OBJECTIVE: Children with relapsed neuroblastoma have a poor prognosis despite modern multimodality therapy. Novel and more effective therapeutic strategies are required for relapsed neuroblastoma. We retrospectively examined the utility of consolidation therapy with high-dose 131I-meta-iodo-benzyl-guanidine (131I-mIBG) in relapsed neuroblastoma or ganglioneuroblastoma patients with complete response (CR) to induction therapy as demonstrated by diagnostic 123I-mIBG scintigraphy. METHODS: Between December 2009 and 2014, five patients with relapsed neuroblastoma and one with relapsed ganglioneuroblastoma received high-dose 131I-mIBG therapy. Overall and progression-free survival rates at five years after 131I-mIBG therapy were analyzed by the Kaplan-Meier method. RESULTS: During follow-up, three children showed no signs of disease relapse, whereas three died. One child without a relapse died from post-transplant side effects, and two children with a relapse died owing to tumor progression. The 5-year progression-free and overall survival rates after 131I-mIBG therapy were 44% and 67%, respectively. CONCLUSIONS: Consolidation therapy with high-dose 131I-mIBG for patients with 2nd CR showed good overall and progression-free survival. While the risks of radiation exposure must be considered, high-dose 131I-mIBG therapy as consolidation therapy needs to be further investigated.

Prognostic Value of Early Evaluation of Left Ventricular Dyssynchrony After Myocardial Infarction.

PURPOSE: Dispersion in the contraction of the normally coordinate ventricular system, referred to as left ventricular (LV) dyssynchrony, is constantly observed at different grades of severity after myocardial infarction (MI). We aimed to investigate the prognostic value of early dyssynchrony in adverse cardiac events after MI in a rat model using the quantified gated single photon emission tomography (SPECT; QGS) software. PROCEDURES: After thoracotomy, the left coronary arteries of 16 rats were occluded and reperfused. SPECT was performed with [99m Tc]methoxyisobutylisonitrile 3 days, 1 week, 2 weeks, 4 weeks, and 8 weeks after MI. The phase analysis parameters including mean phase standard deviation (PSD), bandwidth (BW), entropy, and LV function were analyzed by the QGS software. A receiver operating characteristic curve was used to explore the predictors for cardiac death and severe cardiac failure (ejection fraction [EF] < 35 %). A Kaplan-Meier event-free survival analysis, univariate, and multivariate Cox proportional hazards regression analyses were conducted. RESULTS: Four rats had died, whereas another four rats presented with severe heart failure. LV end-diastolic volume was increased during follow-up, but no significant changes were noted in the other parameters. The prognosis of rats with lower EF and higher end-diastolic and end-systolic volumes (ESV), PSD, BW, and entropy at 3 days after MI was poor. Adverse cardiac events were associated with lower EF (relative risk [RR] 13.1, 95 % confidence Interval [CI]: 2.1-259.9, P = 0.003), higher ESV (RR 6.4, CI 1.4-45.9, P = 0.01), and higher entropy (RR 4.3, 95 % CI: 1.0-21.8, P = 0.04) by univariate analysis. Multivariate analysis showed that lower EF was the most powerful independent predictor of adverse cardiac events (RR 16.0, CI 1.1-429.2, P = 0.03). CONCLUSIONS: Severe early dyssynchrony evaluated by QGS after MI could predict cardiac events in the rat model in the same way as other cardiac function parameters including EF and ESV. The early assessment of dyssynchrony after MI may provide helpful information for the prediction of cardiac events in the future.

Utility of 123I-MIBG Standardized Uptake Value in Patients with Refractory Pheochromocytoma and Paraganglioma.

OBJECTIVES: 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.

Quantification of Myocardial Perfusion Defect Size in Rats: Comparison between Quantitative Perfusion SPECT and Autoradiography.

PURPOSE: Ultra-high resolution single-photon emission computed tomography (SPECT) system, using multiple pinhole collimators, has been applied to the imaging of small rodents. We aimed to compare the myocardial infarction (MI) area on quantitative perfusion single-photon emission computed tomography (QPS; Cedars-Sinai Medical Center, USA) with that on high-resolution autoradiography in rat model to determine the accuracy of perfusion defect measurement by QPS. PROCEDURES: After thoracotomy, rats (n = 9) had their left coronary arteries occluded and reperfused before injection with 185 MBq [99mTc] methoxyisobutylisonitrile ([99mTc]MIBI) for SPECT and autoradiography. Healthy rats (n = 28) were similarly scanned to create a normal database on which to base QPS. The MI area on SPECT images was analysed automatically by QPS software. For the autoradiography images, regions of interest for MI were set at 1 mm intervals. RESULTS: In normal rats, [99mTc]MIBI accumulated throughout the left ventricles, and a polar map of ventricular perfusion showed the lowest and highest uptakes in the inferior (68 % ± 4 %) and anterior (92 % ± 5 %) walls, respectively. In the rat MI model, the percentage of polar map with reduced [99mTc]MIBI uptake correlated strongly with the percentage of left ventricle with MI on autoradiography (r2 = 0.90). CONCLUSIONS: QPS can quantitatively evaluate MI severity on myocardial perfusion images in rats, with comparable results to autoradiography. This widely available software could promote the development of new techniques for analysing cardiac images in small animals.