Evaluation of the total distribution volume of 18F-FBPA in normal tissues of healthy volunteers by non-compartmental kinetic modeling.

OBJECTIVE: Boron neutron capture therapy (BNCT) is a noninvasive radiation therapy method for cancer treatment. In BNCT, 4-borono-2-[18F]-fluoro-L-phenylalanine (18F-FBPA) PET has been employed to estimate 10B accumulation in target tumors and normal tissues if 10B borono-L-phenylalanine (10B-BPA) is used as a boron carrier. The purpose of the current study was to evaluate the total distribution volume (Vt) of 18F-FBPA in normal organs of healthy volunteers by kinetic analysis and to estimate boron concentration in normal organs for the therapeutic dose of 10B-BPA using obtained Vt values. METHODS: Six healthy volunteers were injected with 18F-FBPA (3-5 MBq/kg), and 7 PET-CT scans were performed subsequently. 18F-FBPA radioactivity in whole blood and plasma was measured before, and eight times after the injection. PET images were analyzed by PMOD software. Twelve volumetric regions of interest including the brain, heart, right lung, spleen, liver, parotid salivary glands, esophagus, stomach, pancreas, intestines, and bone marrow were drawn manually for each subject and analyzed with the Logan plot and two Ichise multilinear analyses (MA1 and MA2). The better model was defined by several goodness-of-fit parameters and residual distribution. After Vt values had been derived, boron concentration was estimated in ppm for the 10B-BPA-fructose (10B-BPA-fr) dose 30 g 1 and 2 h post-injection using Vt and interpolated plasma activity data. RESULTS: The Ichise MA2 model showed the best fit among all models. Akaike Information Criterion (AIC) was the lowest for the Ichise's MA2 in all regions (mean AIC value - 14.0) comparing to the other models (Logan plot mean AIC 31.4; Ichise MA1 model mean AIC - 4.2). Mean Vt values of the Ichise MA2 model ranged from 0.94 ± 0.14 ml/ml in the pancreas to 0.16 ± 0.02 ml/ml in the right lung. Estimated boron concentration for 10B-BPA-fr had the highest value in the pancreas (14.0 ± 1.9 ppm 1 h after, and 5.7 ± 1.7 ppm 2 h after the 18F-FBPA administration) and the lowest value in the right lung (2.4 ± 0.3 ppm 1 h, and 1.0 ± 0.3 ppm 2 h post-injection). CONCLUSION: The 10B concentration in normal tissues was best estimated using Vt values of 18F-FBPA with the Ichise multilinear analysis 2 (MA2). TRAIL REGISTRY: The UMIN clinical trial number: UMIN000022850.

Prostacyclin Analogue-Loaded Nanoparticles Attenuate Myocardial Ischemia/Reperfusion Injury in Rats.

Intravenously injected ONO-1301-containing nanoparticles (ONO-1301NPs), unlike an ONO-1301 solution, selectively accumulated in the ischemia/reperfusion (I/R)-injured myocardium of rats and contributed to the prolonged retention of ONO-1301 in the targeted myocardial tissue. In the ischemic area, proangiogenic cytokines were up-regulated and inflammatory cytokines were down-regulated upon ONO-1301NP administration. Consequently, ONO-1301NP-injected rats exhibited a smaller infarct size, better-preserved capillary networks, and a better-preserved myocardial blood flow at 24 h after I/R injury, compared with those in vehicle-injected or ONO-1301 solution-injected rats. ONO-1301NPs attenuate the myocardial I/R injury via proangiogenic and anti-inflammatory effects of the drug.

Preserved Cerebral Oxygen Metabolism in Astrocytic Dysfunction: A Combination Study of 15O-Gas PET with 14C-Acetate Autoradiography.

Fluorocitrate (FC) is a specific metabolic inhibitor of the tricarboxylic acid (TCA) cycle in astrocytes. The purpose of this study was to evaluate whether inhibition of the astrocyte TCA cycle by FC would affect the oxygen metabolism in the rat brain. At 4 h after the intracranial FC injection, the rats (n = 9) were investigated by 15O-labeled gas PET to measure the cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral blood volume (CBV). After the 15O-gas PET, the rats were given an intravenous injection of 14C-acetate for autoradiography. 15O-gas PET showed no significant differences in any of the measured parameters between the ipsilateral and contralateral striatum (high dose group: CBF (54.4 ± 8.8 and 55.3 ± 11.6 mL/100mL/min), CMRO2 (7.0 ± 0.9 and 7.1 ± 1.2 mL/100mL/min), OEF (72.0 ± 8.9 and 70.8 ± 8.2%), and CBV (4.1 ± 0.8 and 4.2 ± 0.9 mL/100mL), respectively). In contrast, the 14C-acetate autoradiography revealed a significant inhibition of the astrocyte metabolism in the ipsilateral striatum. The regional cerebral oxygen consumption as well as the hemodynamic parameters were maintained even in the face of inhibition of the astrocyte TCA cycle metabolism in the rat brain.

Microvascular Dysfunction Related to Progressive Left Ventricular Remodeling due to Chronic Occlusion of the Left Anterior Descending Artery in an Adult Porcine Heart.

Occlusion of a major coronary artery induces myocardial infarction (MI), leading to left ventricle (LV) remodeling due to progressive microvasculature dysfunction. Irreversible impairment in microvascular function has been suggested to extend from the infarcted region into the infarct-border or remote regions, depending on the time to revascularization. Our aim was to determine whether the occlusion of a major coronary artery induces microvascular dysfunction in the adjacent area perfused by intact coronary arteries using a porcine model for chronic total occlusion of the left anterior descending artery (LAD). MI was induced via an ameroid constrictor ring around the LAD in adult Göttingen pigs (Sus scrofa domesticus, n = 5). Age-matched normal pigs were treated as controls (n = 3). Cardiac magnetic resonance showed reduced systolic regional wall motion in the left circumflex (LCx) and right coronary artery (RCA) territories, with a progressively worsening motion in the infarction-adjacent area over an eight-week period. On 13N-ammonia positron emission tomography (PET), myocardial blood flow (MBF) during hyperemia was significantly greater in the LCx and RCA territories (particularly in the infarction-adjacent area) compared to that in the LAD territory at four weeks after infarct induction. Subsequently, the flow significantly decreased, approaching that in the LAD territory at eight weeks after infarct induction. Fluoroscopy-guided pressure-wire studies showed significantly higher microvascular resistance in the LCx area at eight weeks compared to that in controls. Electron microscopy showed endothelium swelling and microvasculature disruption in areas adjacent to the LCx and RCA territories. Anterior MI caused coronary microvascular dysfunction in the adjacent area, associated with a reduced MBF and regional wall motion.

Quantitative measurement of regional cerebral blood flow and oxygen metabolism in a rat model of cerebral hypoperfusion.

This study was aimed at evaluating the regional changes in the cerebral metabolic rate of oxygen (CMRO2) in relation to the cerebral blood flow (CBF) in the bilateral common carotid artery occlusion (BCAO) rat model. Ligation of the bilateral common carotid arteries (or a sham operation in control animals) was performed in 10-week-old male Wistar rats. O-15 PET images were acquired in the subacute phase (1 week after the surgery) and chronic phase (6 weeks after the surgery) with the animals under anesthesia, using a small-animal PET system and the O-15 gas steady-state inhalation method with arterial blood sampling developed in our previous study. Histopathological staining by Klüver-Barrera method and immunocytochemistry staining by glial fibrillary acidic protein were performed. Cognitive function was tested by using the apparatus of Y-maze. Significantly lower CBF and higher oxygen extraction fraction were observed in broad areas of the cerebrum in the subacute phase in the BCAO rats, with recovery in the chronic phase. A stable decrease of the CMRO2 in the subacute phase of arterial occlusion and later was observed in the BCAO rat model, mainly in the anterior cerebral artery territory. Atrophy and rarefaction of corpus callosum were found in the BCAO in the chronic phase. Activity of astrocytes in the BCAO was prominent in the both phases. Working memory was impaired in the BCAO in the chronic phase. Regional changes in cerebral perfusion and oxygen metabolism in the subacute and chronic phases of arterial occlusion were clarified in a rat model of BCAO by quantitative O-15 PET based on the steady-state method.

Distribution of LAT1-targeting PET tracer was independent of the tumor blood flow in rat xenograft models of C6 glioma and MIA PaCa-2.

OBJECTIVE: L-type amino acid transporter 1 (LAT1) is strongly expressed on the cell membrane in various types of human cancer cells, while being minimally expressed in normal or inflammatory tissues. Therefore, LAT1-targeting PET tracers have been developed for cancer-specific imaging. The purpose of this study was to study the distribution of two LAT1-targeting PET tracers, L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) and L-3-18F-alpha-methyl tyrosine (18F-FAMT), in relation to the tumor blood flow, using rat xenograft models. METHODS: Rat tumor xenograft models of C6 glioma (n = 4; tumors = 8) and MIA PaCa-2 (pancreatic cancer) (n = 4; tumors = 6) were used. The expressions of LAT1 and CD98hc were evaluated by both immunofluorescence staining and western blot analysis. Dynamic PET was performed after injection of 18F-FAMT or 18F-FBPA (scan duration = 70 min) following 15O-water PET (scan duration = 10 min). The PET data were subjected to kinetic analyses, and the K1, k2, and total distribution volume (Vt) were calculated using the one-tissue compartment model. The accumulation of the LAT1 tracers was expressed in terms of their Vt. Tumor blood flow (TBF) was represented by the K1 value in 15O-water PET. RESULTS: LAT1/CD98hc expression was confirmed in both xenografts by immunofluorescence staining. Western blot analysis showed higher functional expression of LAT1 in the C6 glioma cells as compared to the MIA PaCa-2 cells (C6 glioma/MIA PaCa-2 relative expression ratio = 1.70). The Vt values of both 18F-FBPA and 18F-FAMT were significantly higher in the C6 glioma xenografts than in the MIA PaCa-2 xenografts (C6 glioma: 2.27 ± 0.35 and 2.03 ± 0.23, respectively; MIA PaCa-2: 1.28 ± 0.26 and 1.35 ± 0.15, respectively). Meanwhile, there was no significant correlation of the Vt value of either 18F-FBPA or 18F-FAMT with the TBF, in either the C6 glioma or the MIA PaCa-2 xenografts. CONCLUSIONS: This study revealed that total distribution volumes of the LAT1-targeting PET tracers 18F-FBPA and 18F-FAMT were independent of the tumor blood flow and might reflect the functional expression levels of LAT1 in the C6 glioma and MIA PaCa-2 xenograft models.

Impact of 18F-PSMA-1007 Uptake in Prostate Cancer Using Different Peptide Concentrations: Preclinical PET/CT Study on Mice.

PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to evaluate the change in the whole-body distribution of 18F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Methods: Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (n = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/µmol; n = 6), a medium-MA group (100.7 ± 23.1 GBq/µmol; n = 6), and a low-MA group (10.80 ± 2.84 GBq/µmol; n = 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUVmean in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney. Results: The low-MA group (SUVmean, 1.12 ± 0.30) showed significantly lower uptake of 18F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUVmean, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUVmean ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney. Conclusion: A decrease in the MA level of the injected 18F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.

Preliminary feasibility study on differential diagnosis between radiation-induced cerebral necrosis and recurrent brain tumor by means of [18F]fluoro-borono-phenylalanine PET/CT.

OBJECTIVES: A previous study reported that a differential diagnosis between glioblastoma progression and radiation necrosis by 4-borono-2-[18F]-fluoro-phenylalanine ([18F]FBPA) PET can be made based on lesion-to-normal ratio of [18F]FBPA accumulation. Two-dimensional data acquisition mode PET alone system, with in-plane resolution of 7.9 mm and axial resolution of 13.9 mm, was used. In the current study, we aimed to confirm the differential diagnostic capability of [18F]FBPA PET/CT with higher PET spatial resolution by three-dimensional visual inspection and by measuring mean standardized uptake value (SUVmean), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion (TL) [18F]FBPA uptake. METHODS: Twelve patients of glioma (9), malignant meningioma (1), hemangiopericytoma (1), and metastatic brain tumor (1) were enrolled. All had preceding radiotherapy. High-resolution three-dimensional data acquisition mode PET/CT with in-plane resolution of 4.07 mm and axial resolution of 5.41 mm was employed for imaging. Images were three-dimensionally analyzed using the PMOD software. SUVmean and SUVmax of lesion and normal brain were measured. Lesion MTV and TL FBPA uptake were calculated. The diagnostic accuracy of [18F]FBPA PET/CT in detecting recurrence (n = 6) or necrosis (n = 6) was verified by clinical follow-up. RESULTS: All parameters showed significantly higher values for tumor recurrence than for necrosis. SUVmean in recurrence was 2.95 ± 0.84 vs 1.18 ± 0.24 in necrosis (P = 0.014); SUVmax in recurrence was 4.63 ± 1.23 vs 1.93 ± 0.44 in necrosis (P = 0.014); MTV in recurrence was 44.92 ± 28.93 mL vs 10.66 ± 8.46 mL in necrosis (P = 0.032); and mean TL FBPA uptake in recurrence was 121.01 ± 50.48 g vs 12.36 ± 9.70 g in necrosis (P = 0.0029). CONCLUSION: In this preliminary feasibility study, we confirmed the possibility of differentiating tumor recurrence from radiation necrosis in patients with irradiated brain tumors by [18F]FBPA PET/CT using indices of SUVmean, SUVmax, MTV, and TL 18FBPA uptake.

A prostacyclin agonist and an omental flap increased myocardial blood flow in a porcine chronic ischemia model.

OBJECTIVE: We hypothesized that therapeutic efficacy may be augmented by a combination of placing a sheet immersed in ONO-1301SR, a slow-release synthetic prostacyclin agonist-inducing multiproangiogenic cytokines, over the left ventricle and a pedicled omental flap in a chronic myocardial infarct heart. METHODS: A minipig chronic myocardial infarction was generated by placing an ameroid constrictor ring around the left anterior descending artery for 4 weeks. The minipigs were then assigned into 4 groups of 6 each: sham, omental flap only, ONO-1301SR only, and ONO-1301SR combined with an omental flap (combined). Four weeks after treatment, therapeutic efficacy was evaluated histologically and via several modalities used in the clinical setting. RESULTS: In an angiogram and pressure wire study, the combined group induced development of collateral arteries to decrease the resistance and increase the flow reserve of microvasculature in the left circumflex territory. In a 13N-ammonia positron emission tomography study, the combined group displayed a prominent increase in myocardial blood flow and myocardial flow reserve in the left circumflex territory, particularly at the infarct-border region. Consequently, the combined group showed greater regional cardiac function in the left circumflex territory particularly at the infarct-border region, contributing to a greater global ejection fraction with a smaller left ventricular endosystolic volume. Pathologically, attenuated fibrosis, nonswollen myocytes, and upgraded capillary density and proangiogenic cytokines were prominent in the combined group. CONCLUSIONS: ONO-1301SR combined with a pedicled omental flap synergistically promoted myocardial angiogenesis, leading to function recovery in a porcine chronic myocardial infarction model.

Oxygen-15 labeled CO2, O2, and CO PET in small animals: evaluation using a 3D-mode microPET scanner and impact of reconstruction algorithms.

BACKGROUND: Positron emission tomography (PET) studies using 15O-labeled CO2, O2, and CO have been used in humans to evaluate cerebral blood flow (CBF), the cerebral oxygen extraction fraction (OEF), and the cerebral metabolic rate of oxygen (CMRO2) and cerebral blood volume (CBV), respectively. In preclinical studies, however, PET studies using 15O-labeled gases are not widely performed because of the technical difficulties associated with handling labeled gases with a short half-life. The aims of the present study were to evaluate the scatter fraction using 3D-mode micro-PET for 15O-labeled gas studies and the influence of reconstruction algorithms on quantitative values. Nine male SD rats were studied using the steady state inhalation method for 15O-labeled gases with arterial blood sampling. The resulting PET images were reconstructed using filtered back projection (FBP), ordered-subset expectation maximization (OSEM) 2D, or OSEM 3D followed by maximum a posteriori (OSEM3D-MAP). The quantitative values for each brain region and each reconstruction method were calculated by applying different reconstruction methods. RESULTS: The quantitative values for the whole brain as calculated using FBP were 46.6 ± 12.5 mL/100 mL/min (CBF), 63.7 ± 7.2% (OEF), 5.72 ± 0.34 mL/100 mL/min (CMRO2), and 5.66 ± 0.34 mL/100 mL (CBV), respectively. The CBF and CMRO2 values were significantly higher when the OSEM2D and OSEM3D-MAP reconstruction methods were used, compared with FBP, whereas the OEF values were significantly lower when reconstructed using OSEM3D-MAP. CONCLUSIONS: We evaluated the difference in quantitative values among the reconstruction algorithms using 3D-mode micro-PET. The iterative reconstruction method resulted in significantly higher quantitative values for CBF and CMRO2, compared with the values calculated using the FBP reconstruction method.

Whole-Body Distribution of Donepezil as an Acetylcholinesterase Inhibitor after Oral Administration in Normal Human Subjects: A 11C-donepezil PET Study.

OBJECTIVES: It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP. METHODS: We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3±4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 µg of DNP, respectively, while one patient was scanned following the oral administration of 30 µg of DNP (group A). Then, we studied five females and five males (48.3±6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT. RESULTS: In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 µg oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 µg of DNP, or no DNP. CONCLUSION: The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP.

Quantitative evaluation of oxygen metabolism in the intratumoral hypoxia: 18F-fluoromisonidazole and 15O-labelled gases inhalation PET.

BACKGROUND: Intratumoral hypoxia is one of the resistant factors in radiotherapy and chemotherapy for cancer. Although it is detected by 18F-fluoromisonidazole (FMISO) PET, the relationship between intratumoral hypoxia and oxygen metabolism has not been studied. The purpose of this study was to evaluate the intratumoral perfusion and oxygen metabolism in hypoxic regions using the rat xenograft model. Ten male Fischer rats with C6 glioma (body weight = 220 ± 15 g) were investigated with 18F-FMISO PET and steady-state inhalation method of 15O-labelled gases PET. The tumoral blood flow (TBF), tumoral metabolic rate of oxygen (TMRO2), oxygen extraction fraction (OEF), and tumoral blood volume (TBV) were measured under artificial ventilation with 15O-CO2, 15O-O2, and 15O-CO gases. Multiple volumes of interest (1-mm diameter sphere) were placed on the co-registered 18F-FMISO (3 h post injection) and functional 15O-labelled gases PET images. The TBF, TMRO2, OEF, and TBV values were compared among the three groups classified by the 18F-FMISO uptake as follows: group Low (L), less than 1.0; group Medium (M), between 1.0 and 2.0; and group High (H), more than 2.0 in the 18F-FMISO standardized uptake value (SUV). RESULTS: There were moderate negative correlations between 18F-FMISO SUV and TBF (r = -0.56 and p < 0.01), and weak negative correlations between 18F-FMISO SUV and TMRO2 (r = -0.38 and p < 0.01) and 18F-FMISO SUV and TBV (r = -0.38 and p < 0.01). Quantitative values were as follows: TBF, (L) 55 ± 30, (M) 32 ± 17, and (H) 30 ± 15 mL/100 mL/min; OEF, (L) 33 ± 14, (M) 36 ± 17, and (H) 41 ± 16%; TMRO2, (L) 2.8 ± 1.3, (M) 1.9 ± 1.0, and (H) 2.1 ± 1.1 mL/100 mL/min; and TBV, (L) 5.7 ± 2.1, (M) 4.3 ± 1.9, and (H) 3.9 ± 1.2 mL/100 mL, respectively. Intratumoral hypoxic regions (M and H) showed significantly lower TBF, TMRO2, and TBV values than non-hypoxic regions (L). OEF showed significant increase in the severe hypoxic region compared to non-hypoxic and mild hypoxic regions. CONCLUSIONS: This study demonstrated that intratumoral hypoxic regions showed decreased blood flow with increased oxygen extraction, suggesting the need for a treatment strategy to normalize the blood flow for oxygen-avid active tumor cells in hypoxic regions.

A new shielding calculation method for X-ray computed tomography regarding scattered radiation.

The goal of this study is to develop a more appropriate shielding calculation method for computed tomography (CT) in comparison with the Japanese conventional (JC) method and the National Council on Radiation Protection and Measurements (NCRP)-dose length product (DLP) method. Scattered dose distributions were measured in a CT room with 18 scanners (16 scanners in the case of the JC method) for one week during routine clinical use. The radiation doses were calculated for the same period using the JC and NCRP-DLP methods. The mean (NCRP-DLP-calculated dose)/(measured dose) ratios in each direction ranged from 1.7 ± 0.6 to 55 ± 24 (mean ± standard deviation). The NCRP-DLP method underestimated the dose at 3.4% in fewer shielding directions without the gantry and a subject, and the minimum (NCRP-DLP-calculated dose)/(measured dose) ratio was 0.6. The reduction factors were 0.036 ± 0.014 and 0.24 ± 0.061 for the gantry and couch directions, respectively. The (JC-calculated dose)/(measured dose) ratios ranged from 11 ± 8.7 to 404 ± 340. The air kerma scatter factor κ is expected to be twice as high as that calculated with the NCRP-DLP method and the reduction factors are expected to be 0.1 and 0.4 for the gantry and couch directions, respectively. We, therefore, propose a more appropriate method, the Japanese-DLP method, which resolves the issues of possible underestimation of the scattered radiation and overestimation of the reduction factors in the gantry and couch directions.

Comparison of the image-derived radioactivity and blood-sample radioactivity for estimating the clinical indicators of the efficacy of boron neutron capture therapy (BNCT): 4-borono-2-18F-fluoro-phenylalanine (FBPA) PET study.

BACKGROUND: In boron neutron capture therapy (BNCT), positron emission tomography (PET) with 4-borono-2-18F-fluoro-phenylalanine (FBPA) is the only method to estimate an accumulation of 10B to target tumor and surrounding normal tissue after administering 10B carrier of L-paraboronophenylalanine and to search the indication of BNCT for individual patient. Absolute concentration of 10B in tumor has been estimated by multiplying 10B concentration in blood during BNCT by tumor to blood radioactivity (T/B) ratio derived from FBPA PET. However, the method to measure blood radioactivity either by blood sampling or image data has not been standardized. We compared image-derived blood radioactivity of FBPA with blood sampling data and studied appropriate timing and location for measuring image-derived blood counts. METHODS: We obtained 7 repeated whole-body PET scans in five healthy subjects. Arterialized venous blood samples were obtained from the antecubital vein, heated in a heating blanket. Time-activity curves (TACs) of image-derived blood radioactivity were obtained using volumes of interest (VOIs) over ascending aorta, aortic arch, pulmonary artery, left and right ventricles, inferior vena cava, and abdominal aorta. Image-derived blood radioactivity was compared with those measured by blood sampling data in each location. RESULTS: Both the TACs of blood sampling radioactivity in each subject, and the TACs of image-derived blood radioactivity showed a peak within 5 min after the tracer injection, and promptly decreased soon thereafter. Linear relationship was found between blood sampling radioactivity and image-derived blood radioactivity in all the VOIs at any timing of data sampling (p < 0.001). Image-derived radioactivity measured in the left and right ventricles 30 min after injection showed high correlation with blood radioactivity. Image-derived blood radioactivity was lower than blood sampling radioactivity data by 20 %. Reduction of blood radioactivity of FBPA in left ventricle after 30 min of FBPA injection was minimal. CONCLUSION: We conclude that the image-derived T/B ratio can be reliably used by setting the VOI on the left ventricle at 30 min after FBPA administration and correcting for underestimation due to partial volume effect and reduction of FBPA blood radioactivity.

Assessment of 10B concentration in boron neutron capture therapy: potential of image-guided therapy using 18FBPA PET.

OBJECTIVES: In boron neutron capture therapy (BNCT) for cancer, the accurate estimation of 10B tissue concentrations, especially in neighboring normal organs, is important to avoid adverse effects. The 10B concentration in normal organs after loading with 10B, however, has not been established in humans. In this study, we performed 4-borono-2-[18F]-fluoro-phenylalanine (18FBPA) PET in healthy volunteers and estimated the chronological changes in the 10B concentrations of normal organs. METHODS: In 6 healthy volunteers, whole-body 18FBPA PET scans were repeated 7 times during 1 h, and the mean 18FBPA distributions of 13 organs were measured. Based on the 18FBPA PET data, we then estimated the changes in the 10B concentrations of the organs when the injection of a therapeutic dose of 10BPA-fructose complex (10BPA-fr; 30 g, 500 mg/kg body weight) was assumed. RESULTS: The maximum mean 18FBPA concentrations were reached at 2-6 min after injection in all the organs except the brain and urinary bladder. The mean 18FBPA concentration in normal brain plateaued at 24 min after injection. When the injection of a therapeutic dose of 10BPA-fr was assumed, the estimated mean 10B concentration in the kidney increased to 126.1 ± 24.2 ppm at 3 min after injection and then rapidly decreased to 30.9 ± 7.4 ppm at 53 min. The estimated mean 10B concentration in the bladder gradually increased and reached 383.6 ± 214.7 ppm at 51 min. The mean 10B concentration in the brain was estimated to be 7.6 ± 1.5 ppm at 57 min. CONCLUSIONS: 18FBPA PET has a potential to estimate 10B concentration of normal organs before neutron irradiation of BNCT when several assumptions are validated in the future studies.

Assessing the Effectiveness of Risk Communication for Maintenance Workers Who Deal With Induced Radioactivity Management of Medical Linear Accelerators.

In Japan, an amended law that mandates levels of unintended induced radioactivity has been in effect since 1 April 2012. According to the new regulation, if the concentration of induced radioactivity in affected parts is above the clearance level, the parts must be regarded as radioactive even if they weigh less than 1 kg. This regulation reform raises several new issues concerning medical linear accelerators, including how to determine the decay period for induced radioactivity before maintenance can be performed and how to identify what parts should be considered radioactive waste. The authors performed several risk communication (RC) activities aimed at improving the understanding of maintenance workers at medical accelerator manufacturers and establishing good guidelines by involving stakeholders. For this purpose, a working group was established and conducted RC activities, such as holding opinion exchange meetings between medical staff and maintenance workers and creating a booklet to answer questions from maintenance workers. To evaluate these activities, three questionnaire surveys were conducted between 2011 and 2014. According to the results of this study, the ratio of maintenance workers who accepted "The decay period is within one week" was approximately 60% at the third survey and significantly increased (P < 0.0001) during the survey period. Approximately 25% of the maintenance workers felt that not enough information was provided about the decay period, and approximately 63% thought that the information provided on the health effects of radiation was sufficient. These results suggest that the present RC was successful.

Cell-sheet therapy with omentopexy promotes arteriogenesis and improves coronary circulation physiology in failing heart.

Cell-sheet transplantation induces angiogenesis for chronic myocardial infarction (MI), though insufficient capillary maturation and paucity of arteriogenesis may limit its therapeutic effects. Omentum has been used clinically to promote revascularization and healing of ischemic tissues. We hypothesized that cell-sheet transplantation covered with an omentum-flap would effectively establish mature blood vessels and improve coronary microcirculation physiology, enhancing the therapeutic effects of cell-sheet therapy. Rats were divided into four groups after coronary ligation; skeletal myoblast cell-sheet plus omentum-flap (combined), cell-sheet only, omentum-flap only, and sham operation. At 4 weeks after the treatment, the combined group showed attenuated cardiac hypertrophy and fibrosis, and a greater amount of functionally (CD31(+)/lectin(+)) and structurally (CD31(+)/α-SMA(+)) mature blood vessels, along with myocardial upregulation of relevant genes. Synchrotron-based microangiography revealed that the combined procedure increased vascularization in resistance arterial vessels with better dilatory responses to endothelium-dependent agents. Serial (13)N-ammonia PET showed better global coronary flow reserve in the combined group, mainly attributed to improvement in the basal left ventricle. Consequently, the combined group had sustained improvements in cardiac function parameters and better functional capacity. Cell-sheet transplantation with an omentum-flap better promoted arteriogenesis and improved coronary microcirculation physiology in ischemic myocardium, leading to potent functional recovery in the failing heart.

Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholinesterase activity in the adrenal gland: 11C-donepezil PET study in the normal rat.

PURPOSE: Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered (11)C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. METHODS: The distribution of (11)C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220 ± 8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of (11)C-DNP (45.0 ± 10.7 MBq). The whole-body distribution of the (11)C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. RESULTS: The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of (11)C-DNP in the body (following the liver) (13.33 ± 1.08 and 19.43 ± 1.29 ml/cm(3), respectively), indicating that the distribution of (11)C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9 ± 1.6, 83.1 ± 3.0, and 38.5 ± 8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. CONCLUSIONS: We demonstrated the whole-body distribution of (11)C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of (11)C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.

Preoperative evaluation of venous anatomy in laparoscopic complete mesocolic excision for right colon cancer.

PURPOSE: This study evaluated the venous variations of the right colon using preoperative three-dimensional computed tomography (3D-CT), and to investigate its usefulness in laparoscopic complete mesocolic excision (CME) for right colon cancer. METHODS: 3D-CT was performed prior to surgery in 81 consecutive patients with right colon cancer. RESULTS: Laparoscopic right hemicolectomy was performed without conversion to open surgery in all cases (100 %). All 81 patients had a single ileocolic vein (ICV). The ICV flowed into the superior mesenteric vein (SMV) in 98 % of patients and the gastrocolic trunk (GCT) in 2 % of patients. The right colic vein (RCV) was absent in 6 % of patients. One RCV was present in 88 % of patients and two were present in 6 % of patients. The main RCV flowed into the GCT in 84 % of patients and the SMV in 10 % of patients. The superior RCV was present in 21 % of patients, and all cases flowed into the GCT. One middle colic vein (MCV) was present in 49 % of patients, two in 46 %, and three in 5 % of patients. The main MCV flowed into the SMV in 68 % of patients, GCT in 20 %, jejunal vein in 6 %, inferior mesenteric vein in 5 %, and the splenic vein in 1 % of patients. The GCT was present in 88 % of patients. CONCLUSIONS: Although the venous tributaries of the right colon are variable, preoperative 3D-CT is informative and helpful for surgeons performing laparoscopic CME for right colon cancer.