Makoto Fukuoka

Comparison of diagnostic value of I-123 MIBG and high-dose I-131 MIBG scintigraphy including incremental value of SPECT/CT over planar image in patients with malignant pheochromocytoma/paraganglioma and neuroblastoma.

Purpose: To compare lesion detectability of I-123 MIBG scintigraphy with that of high-dose I-131 MIBG and to evaluate incremental benefit of SPECT/CT over planar image for the detection and localization of the lesions in patients with I-131 MIBG therapy for malignant pheochromocytoma/paraganglioma and neuroblastoma. Materials and Methods: We retrospectively investigated 16 patients with malignant pheochromocytoma/paraganglioma and neuroblastoma, who were referred for I-131 MIBG therapy. We investigated the lesion detectability in 10 pairs of I-123 and high-dose I-131 MIBG studies of the same patient, obtained within 2 weeks. In 31 studies of I-123 MIBG scintigraphy in 16 patients and 17 studies of high-dose I-131 MIBG scintigraphy in 12 patients, we compared planar and SPECT/CT images for the lesion detectability and localization. Results: The number of lesions detected by I-123 MIBG planer image and SPECT/CT and high-dose planer I-131 MIBG and SPECT/CT were 3.0 and 3.7, 7.3 and 7.7 per study, respectively. SPECT/CT images provided additional diagnostic information over planar images in 25 studies (81%) of 12 patients (75%) in I-123 MIBG scintigraphy and in 9 studies (53%) of 9 patients (75%) in high-dose I-131 MIBG scintigraphy. Conclusion: Post-therapy high-dose I-131 MIBG scintigraphy is superior to I-123 MIBG scintigraphy in lesion detectability even in comparison with I-123 MIBG SPECT/CT images and high-dose I-131 MIBG planar images in patients with malignant neuroendocrine tumors. SPECT/CT images are helpful for accurate identification of anatomic localization compared with planar images.

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.

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.

99mTc-sestamibi to monitor treatment with antisense oligodeoxynucleotide complementary to MRP mRNA in human breast cancer cells

ObjectiveTechnetium-99m sestamibi (MIBI) has been utilized to evaluate multi-drug resistance (MDR) phenomenon of malignant tumors and to predict chemotherapeutic effects on them. The current investigation examined the possibility of monitoring changes with respect to mRNA expression of multi-drug resistance associated protein (MRP) following antisense oligodeoxynucleotide (AS-ODN) treatment involving99mTc-MIBI.MethodsThe human breast cancer MCF-7 cell line and its MDR-induced MCF-7/VP cell line were employed. Cell suspensions of the two cell lines at 1 x 104 cells/m/ were inoculated in 24-well plates (0.2 ml/well) and incubated for one day. Antisense (AS) 20-mer phosphorothioate ODN complementary to the coding region of MRP mRNA and its sense (S) ODN were administered at final concentrations up to 25 μM, followed by a 5-day incubation.99mTc-MIBI solution was added to each well and incubated for 30 min. Cellular99mTc-MIBI uptake was corrected for protein concentration. MRP mRNA expression levels were analyzed via the reverse transcription Polymerase chain reaction (RT-PCR).ResultsCellular uptake of99mTc-MIBI in MCF-7/VP cells was only 15% of that of MCF-7 cells. Following AS-ODN treatment at 25 μM for five days,99mTc-MIBI uptake in MCF-7/VP cells increased 2.4-fold in comparison with non-treated control cells.99mTc-MIBI uptake in MCF-7 cells was unaffected by AS-ODN administration. Sense ODN did not alter uptake in either cell line. RT-PCR confirmed reduction of MRP mRNA in MCF-7/VP cells following AS-ODN treatment.ConclusionEffects of AS-ODN administration on MRP function can be monitored via assessment of cellular uptake of99mTc-MIBI.

Anti-angiogenic therapy and chemotherapy affect 99mTc sestamibi and 99mTc-HL91 accumulation differently in tumour xenografts.

BackgroundFavourable effects of cytotoxic chemotherapy for tumours are characterized by the reduced accumulation of radiotracers such as 99mTc sestamibi (MIBI). Anti-angiogenic therapy is primarily cytostatic; consequently, its influence on tracer accumulation may differ from that of cytotoxic treatments. MethodsAnti-angiogenic therapy employing 2-methoxyestradiol was administered in mice bearing subcutaneous xenografts of LS180 colon cancer cells. The effects of chemotherapy with 5-fluorouracil were examined as a cytotoxic counterpart. Treatments were conducted for 4 days from day 8. Distribution of 99mTc-MIBI and 99mTc-HL91, a hypoxic marker, was observed on days 8 and 12. Oxygen tension (PO2) in tumours was measured by a microelectrode. Cellular uptake of tracers was examined in vitro in normoxic and hypoxic conditions. Results99mTc-MIBI accumulation decreased with increasing tumour weight when no treatment was conducted. Tumour growth was suppressed by anti-angiogenic therapy and chemotherapy. 99mTc-MIBI accumulation in tumours decreased after chemotherapy as compared to pre-therapeutic values, whereas accumulation of 99mTc-HL91 increased. In contrast, accumulation of tracers did not significantly change after anti-angiogenic therapy as compared to that observed pre-therapeutically. Tumour PO2 decreased with increasing tumour volume when no treatment was conducted. Chemotherapy reduced PO2 in tumours. PO2 in tumours treated with anti-angiogenic therapy was as high as that observed before treatment. 2-Methoxyestradiol or 5-fluorouracil did not significantly affect tracer accumulation in cells under both normoxic and hypoxic conditions in vitro. ConclusionThese findings indicate that scintigraphic assessment of therapeutic efficacy of anti-angiogenic therapy should be performed from a perspective distinct from that of cytotoxic treatment.

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.

Thyroid hormone replacement one day before 131I therapy in patients with well-differentiated thyroid cancer

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 thyroglobulin 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.

Fluctuation of adenosine concentration by modes of intravenous infusion based on mathematical simulation and experiments

ObjectiveAdenosine, which has been used for a myocardial perfusion scan, shows rapid clearance from blood because of its short half-life of <10 seconds. This simulation study evaluates influences of modes of radionuclide injection on ventricular adenosine concentration when one intravenous injection line is used.MethodsAssuming that radionuclide injection is a unit impulse, time-activity curves were measured in the left ventricle (LV) and fitted by a gamma function. Typical patterns of concentration fluctuation when adenosine infusion was temporarily modified were calculated by the convolution integral of input function and unit impulse response. Variation of concentration was measured by experiments using continuous99mTc injection and co-infusion of water via a three-way stopcock. Modes of co-infusion with various infusion speeds and volumes were examined.ResultsIntermission of adenosine infusion and rapid displacement by radionuclide co-injection significantly influenced the adenosine concentration in LV. Intermission of adenosine infusion for 2 seconds caused a 15% decrease in the adenosine concentration in the left ventricle. When a square-shaped input was assumed, a three-fold higher concentration of adenosine for 3 seconds created by radionuclide injection resulted in a +42% increase in the LV concentration. Based on a measured input function, radionuclide injection using three-way stopcock through one route caused a two- to three-fold increase in the steady concentration in the vein just after injection. When 0.5 ml of radionuclide was slowly co-injected, with three ways opened, it caused a relatively low fluctuation, creating a +34% to -47% change in concentration of LV. A flush of radionuclide with physiological saline significantly increased the adenosine concentration in LV, when short half-lives were assumed.ConclusionAn intravenous adenosine and radiopharmaceutical injection in the same line is feasible. However, the fluctuation of concentration depends significantly on the mode of injection. To minimize the fluctuation, a slow injection of a small volume of a myocardial imaging agent via a co-injection route, with three ways opened, is recommended.