Daiki Kayano

Effect of Postconditioning on Myocardial 99mTc-Annexin-V Uptake: Comparison with Ischemic Preconditioning and Caspase Inhibitor Treatment

99mTc-Annexin-V imaging has been proved to be feasible to detect phosphatidylserine, which externalizes on the outer cell membrane early in the process of apoptosis. To determine whether postconditioning suppresses myocardial cell damage or apoptosis, we evaluated the intensity and distribution of 99mTc-annexin-V uptake after postconditioning in a rat model of ischemia and reperfusion and compared the effect to that of ischemic preconditioning and pretreatment with caspase inhibitor. Methods: In control rats (n = 13), after thoracotomy the left coronary artery was occluded for 20 min followed by reperfusion for 30 or 90 min and injection of 99mTc-annexin-V (80–150 MBq). One hour later, to verify the area at risk, 201Tl (0.74 MBq) was injected intravenously just beyond the left coronary artery reocclusion, and the rats were sacrificed 1 min later. In the groups of rats with various interventions, postconditioning (n = 11) was performed just after the reperfusion, and preconditioning (n = 11) and caspase inhibitor treatment (n = 11) were performed before ischemia. Dual-tracer autoradiography was performed to assess 99mTc-annexin-V uptake and area at risk. Results: In all control rats, intense 99mTc-annexin-V uptake was observed in the area at risk (uptake ratios at 30 or 90 min after reperfusion, 4.15 ± 1.89 and 3.70 ± 1.41, respectively). Postconditioning suppressed 99mTc-annexin-V uptake (uptake ratios at 30 or 90 min after reperfusion, 2.09 ± 0.56, P < 0.05, and 1.88 ± 0.69, P < 0.05, respectively). Preconditioning also suppressed uptake (uptake ratios at 30 and 90 min after reperfusion, 1.17 ± 0.29, P < 0.005, and 1.33 ± 0.74, P < 0.01, respectively), as did caspase inhibitor (uptake ratios at 30 and 90 min after reperfusion, 2.08 ± 0.50, P < 0.05, and 1.27 ± 0.24, P < 0.005, respectively). In all interventions, the percentage of cells positive on deoxyuride-5′-triphosphate biotin nick end labeling and histologic changes with myocardial cell degeneration and cell infiltrations were suppressed markedly. Conclusion: These data indicate that 99mTc-annexin-V imaging may be a way to monitor myocardial injury and its response to novel therapeutic interventions including postconditioning, preconditioning, and antiapoptotic therapy.

Effects and safety of 131I-metaiodobenzylguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors: Results from a multicenter observational registry

Effective treatments for malignant neuroendocrine tumors are under development. While iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) radiotherapy has been used in the treatment of malignant neuroendocrine tumors, there are few studies evaluating its therapeutic effects and safety in a multicenter cohort. In the current study, we sought to evaluate the effects and safety of ¹³¹I-MIBG therapy for conditions including malignant pheochromocytoma and paraganglioma within a multicenter cohort. Forty-eight malignant neuroendocrine tumors (37 pheochromocytoma and 11 paraganglioma) from four centers underwent clinical ¹³¹I-MIBG radiotherapy. The tumor responses were observed before and 3 to 6 months after the ¹³¹I-MIBG radiotherapy in accordance with RECIST criteria. We also evaluated the data for any adverse effects. The four centers performed a total of 87 ¹³¹I-MIBG treatments on 48 patients between January 2000 and March 2009. Of the treatments, 65 were evaluable using RECIST criteria. One partial response (PR), 40 stable disease (SD), and 9 progressive disease (PD) in malignant pheochromocytoma were observed after each treatment. Fourteen SD and one PD-were observed in paraganglioma. Patients with normal hypertension (systolic blood pressure (BP) > 130 mmHg) showed significantly reduced systolic BP after the initial follow-up (n=10, 138.1±8.2 to 129.5±13.5 mmHg, P=0.03). In adult neuroendocrine tumors with a treatment-basis analysis, there were side effects following 41 treatments (47.1%) and most of them (90.2%) were minor. In this multicenter registry, PR or SD was achieved in 84.6% of the treatment occasions in adult neuroendocrine tumors through ¹³¹I-MIBG radiotherapy. This indicated that most of the ¹³¹I-MIBG radiotherapy was performed safely without significant side effects.

Efficacy of diflunisal on autonomic dysfunction of late-onset familial amyloid polyneuropathy (TTR Val30Met) in a Japanese endemic area.

OBJECTIVE To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area. METHODS Consecutive six FAP patients (mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and (123)iodine-metaiodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy. RESULTS One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3-5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on (123)I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated. CONCLUSION Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation.

Iodine-131 Metaiodobenzylguanidine Therapy for Neuroblastoma: Reports So Far and Future Perspective

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.

Tc-99m human serum albumin lymphoscintigraphy with SPECT/CT in chylothorax.

Abstract:A 45-year-old man who had refractory right chylothorax after esophagectomy for esophageal cancer, underwent lymphoscintigraphy with Tc-99m human serum albumin. Focal abnormal uptake was seen in the mid-abdomen on planar image 30 minutes after the tracer injection. SPECT/CT delineated the ex

Low-dose 123I-metaiodobenzylguanidine diagnostic scan is inferior to 131I-metaiodobenzylguanidine posttreatment scan in detection of malignant pheochromocytoma and paraganglioma

ObjectiveWe assessed the lesion detectability of low-dose diagnostic 123I-metaiodobenzylguanidine (MIBG) whole-body scans obtained at 6 and 24 h compared with posttreatment 131I-MIBG whole-body scans in malignant pheochromocytoma and paraganglioma. MethodsScintigrams obtained in 15 patients with malignant pheochromocytoma and paraganglioma were retrospectively analyzed. Diagnostic scans were performed with 111 MBq of 123I-MIBG. Therapeutic doses of 131I-MIBG (5.55–7.40 GBq) were administrated and whole-body scans were obtained at 2–5 days after 131I-MIBG administrations. We compared the number of lesions and the lesion-to-referent count ratios at 6 and 24 h of 123I-MIBG and at 2–5 days of 131I-MIBG. ResultsIn comparison with the 6-h images of 123I-MIBG, the 24-h images of 123I-MIBG could detect more lesions in eight patients. Posttreatment 131I-MIBG scans revealed new lesions in eight patients compared with the 24-h images of 123I-MIBG. The lesion-to-referent count ratios at 6 and 24 h of 123I-MIBG and at 3 days of 131I-MIBG were increasing at later scanning time. There were significant differences in the lesion-to-referent count ratios between 6 and 24 h of 123I-MIBG (P = 0.031), 6 h of 123I-MIBG and 3 days of 131I-MIBG (P = 0.020), and 24 h of 123I-MIBG and 3 days of 131I-MIBG (P = 0.018). ConclusionLow-dose diagnostic 123I-MIBG whole-body scan is inferior to posttreatment 131I-MIBG whole-body scan in malignant pheochromocytoma and paraganglioma. Considering the scan timing of 123I-MIBG, 6-h images might have no superiority compared with 24-h images.

I-131 uptake in a thymic cyst

A 61-year old woman after total thyroidectomy for papillary thyroid cancer underwent I-131 therapy. Focal uptake was seen in the chest on whole body imaging. SPECT/CT delineated I-131 accumulation in an iso-dense mediastinal lesion which was histologically diagnosed as thymic cyst. I-131 uptake in thymic cyst has never been reported and should be included in the gamut of false positive entities of I-131 scintigraphy.

Gated myocardial perfusion SPECT for preoperative risk stratification in patients with noncardiac vascular disease

ObjectiveMyocardial perfusion single photon emission computed tomography (SPECT) is useful for preoperative cardiac risk stratification. We investigated the value of preoperative pharmacologic stress electrocardiographic (ECG)-gated myocardial perfusion SPECT for noncardiac vascular surgery.MethodsTo assess the perioperative cardiac risk for noncardiac vascular surgery, preoperative pharmacologic stress ECG-gated myocardial perfusion SPECT was performed in 211 consecutive patients who underwent noncardiac aortic surgery. We examined myocardial perfusion and left ventricular function by the quantitative gated SPECT (QGS), and the correlation with perioperative cardiac events was investigated.ResultsPerioperative cardiac events occurred in 9 of 211 patients (4.3%). On the basis of univariate analysis, significant predictors for preoperative cardiac risk stratification included history of heart failure (P < 0.05), history of coronary artery revascularization (P < 0.05), summed stress score (SSS) (P < 0.0001), summed rest score (SRS) (P < 0.005), SSS ≥ 7 (P < 0.005), end-diastolic volume (EDV) ≥ mean + 2 standard deviation (SD) (134 ml for men and 93 ml for women) (P < 0.005), end-systolic volume (ESV) ≥ mean + 2 SD (60 ml for men and 37 ml for women) (p < 0.0001), left ventricular ejection fraction (EF) ≤ mean − 2 SD (48% for men and 55% for women) (P < 0.005) and wall motion abnormality (P < 0.05). On the basis of multivariate analysis, ESV ≥ mean + 2 SD was the only independent predictor for perioperative cardiac events (P < 0.005).ConclusionsPharmacologic stress ECG-gated myocardial perfusion SPECT, which permits assessment of both myocardial perfusion and cardiac function, is useful for preoperative risk stratification of noncardiac vascular surgery.

Prototype imaging protocols for monitoring the efficacy of iodine-131 ablation in differentiated thyroid cancer.

Whole-body and single photon emission tomography (SPET) images during sodium iodide-131 (Na131I) ablation are useful to confirm the efficacy of ablation using 131I imaging. However, there have been no attempts to improve the quality of 131I imaging. We therefore investigated imaging protocols for 131I imaging in differentiated thyroid cancer (DTC). Phantoms containing 131I were used to simulate extra-thyroid beds and thyroid beds. To simulate extra-thyroid beds, a phantom containing 0.19, 0.37, 0.74 or 1.85 MBq was placed in the acquisition center. To simulate the thyroid beds, four phantoms were applied as normal thyroid tissue, and four phantoms containing 0.19, 0.37, 0.74 and 1.85 MBq were arranged around normal thyroid tissue as a cancer. Whole-body imaging was performed at different table speeds, and SPET data acquired with various pixel sizes were reconstructed using a filtered backed projection (FBP) and ordered-subsets expectation maximization with 3-dimensional (OSEM-3D) algorithm. We measured full width at half maximum (FWHM) and % coefficient of variation (%CV). Patients were then examined based on the results of phantom studies. In extrathyroid beds, slower table speed in whole-body imaging improved %CV, but had little effect on FWHM. For SPET imaging OSEM-3D produced high-resolution and low-noise images, and FWHM and %CV improved with smaller pixel size, as compared with FBP. In the thyroid beds, only the 1.85 MBq phantom could be confirmed on whole-body imaging. Images by SPET had high FWHM and low %CV when the smaller pixel size and OSEM-3D were applied. Accumulation of ≤1.85 MBq was detected with a smaller pixel size of ≤4.8 mm and OSEM-3D. For Na131I ablation imaging, slower scan speed is suitable for whole-body imaging and smaller pixel size and OSEM-3D is appropriate for SPET imaging. In conclusion, we confirmed Na131I accumulation in thyroid beds using slower scan speed (≤15 cm/min) on whole-body imaging, and then accurate identification of Na131I accumulation using SPET and CT fusion imaging with smaller pixel size (≤4.8 mm) and OSEM-3D.

I-131-Metaiodobenzylguanidine therapy with allogeneic cord blood stem cell transplantation for recurrent neuroblastoma.

Iodine-131-metaiodiobenzylguanidine (131I-MIBG) therapy combined with allogeneic cord blood stem cell transplantation (SCT) was used to treat a 4-year-old girl with recurrent neuroblastoma. The patient experienced relapse 2 years after receiving first-line therapies, which included chemotherapy, surgical resection, irradiation, and autologous peripheral SCT. Although 131I-MIBG treatment did not achieve complete remission, the size of the tumor was reduced after treatment. Based on our findings, we suggest that 131I-MIBG treatment with myeloablative allogeneic SCT should be considered as first-line therapy for high-risk neuroblastoma patients when possible.