Keiichi Magota

High Reproducibility of Tumor Hypoxia Evaluated by 18F-Fluoromisonidazole PET for Head and Neck Cancer

Tumor hypoxia is well known to be radiation resistant. 18F-fluoromisonidazole (18F-FMISO) PET has been used for noninvasive evaluation of hypoxia. Quantitative evaluation of 18F-FMISO uptake is thus expected to play an important role in the planning of dose escalation radiotherapy. However, the reproducibility of 18F-FMISO uptake has remained unclarified. We therefore investigated the reproducibility of tumor hypoxia by using quantitative analysis of 18F-FMISO uptake. Methods: Eleven patients with untreated head and neck cancer underwent 2 18F-FMISO PET/CT scans (18F-FMISO1 and 18F-FMISO2) with a 48-h interval prospectively. All images were acquired at 4 h after 18F-FMISO injection for 10 min. The maximum standardized uptake (SUVmax), tumor-to-blood ratio (TBR), and tumor-to-muscle ratio (TMR) of 18F-FMISO uptake were statistically compared between the 2 18F-FMISO scans by use of intraclass correlation coefficients (ICCs). The hypoxic volume was calculated as the area with a TBR of greater than or equal to 1.5 or the area with a TMR of greater than or equal to 1.25 to assess differences in hypoxic volume between the 2 18F-FMISO scans. The distances from the maximum uptake locations of the 18F-FMISO1 images to those of the 18F-FMISO2 images were measured to evaluate the locations of 18F-FMISO uptake. Results: The SUVmax (mean ± SD) for 18F-FMISO1 and 18F-FMISO2 was 3.16 ± 1.29 and 3.02 ± 1.12, respectively, with the difference between the 2 scans being 7.0% ± 4.6%. The TBRs for 18F-FMISO1 and 18F-FMISO2 were 2.98 ± 0.83 and 2.97 ± 0.64, respectively, with a difference of 9.9% ± 3.3%. The TMRs for 18F-FMISO1 and 18F-FMISO2 were 2.25 ± 0.71 and 2.19 ± 0.67, respectively, with a difference of 7.1% ± 5.3%. The ICCs for SUVmax, TBR, and TMR were 0.959, 0.913, and 0.965, respectively. The difference in hypoxic volume based on TBR was 1.8 ± 1.8 mL, and the difference in hypoxic volume based on TMR was 0.9 ± 1.3 mL, with ICCs of 0.986 and 0.996, respectively. The maximum uptake locations of the 18F-FMISO1 images were different from those of the 18F-FMISO2 images and were within the full width at half maximum of the PET/CT scanner, except in 1 case. Conclusion: The values for 18F-FMISO PET uptake and hypoxic volume in head and neck tumors between the 2 18F-FMISO scans were highly reproducible. Such high reproducibility of tumor hypoxia is promising for accurate radiation planning.

Bone Marrow Stromal Cell Transplantation Enhances Recovery of Local Glucose Metabolism After Cerebral Infarction in Rats: A Serial 18F-FDG PET Study

This study aimed to assess whether 18F-FDG PET could serially monitor the beneficial effects of bone marrow stromal cells (BMSC) on cerebral glucose metabolism when transplanted into the infarct brain of rats. Methods: The BMSC from green fluorescent protein transgenic rats or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 d after permanent middle cerebral artery occlusion of rats. Local glucose metabolism was semiquantitatively measured at 6 and 35 d after ischemia using 18F-FDG PET. Motor function was serially evaluated throughout the experiments. At 35 d after ischemia, immunohistochemistry was performed to evaluate the phenotype of BMSC and their effects on the expression of brain-type glucose transporters. Results: BMSC transplantation not only enhanced functional recovery but also promoted the recovery of glucose utilization in the periinfarct area when stereotactically transplanted at 1 wk after ischemia. The engrafted cells were widely distributed, and most expressed a neuron-specific protein, NeuN. BMSC transplantation also prevented the pathologic upregulation of glucose transporters in the periinfarct neocortex. Conclusion: The present findings strongly suggest that the BMSC may enhance functional recovery by promoting the recovery of local glucose metabolism in the periinfarct area when directly transplanted into the infarct brain at clinically relevant timing. The BMSC also inhibit the pathologic upregulation of brain-isoform glucose transporters type 1 and 3. 18F-FDG PET may be a valuable modality to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situations.

Validity of Dual MRI and 18F-FDG PET Imaging in Predicting Vulnerable and Inflamed Carotid Plaque

Background: Vulnerable and inflamed plaques in the carotid artery are at high risk of ischemic stroke, suggesting the importance of diagnostic modalities to detect them in patients with carotid stenosis with high sensitivity and specificity. Although many investigators have reported that magnetic resonance imaging (MRI) is a useful tool to predict the vulnerable components of carotid plaque, its validity is not established. On the other hand, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) may be an alternative modality to directly identify the inflamed plaque in carotid artery stenosis. Therefore, this study aimed at evaluating the validity of MRI and FDG-PET to predict vulnerable and inflamed carotid plaque. Methods: This prospective study totally included 25 patients who underwent carotid endarterectomy (CEA) for carotid artery stenosis at our institute between January 2009 and January 2012. Prior to CEA, FDG-PET, black-blood T1-weighted imaging (BB-T1WI), and 3-dimensional time-of-flight (TOF) imaging were performed. The specimens were stained with hematoxylin-eosin to assess the different plaque components (lipid, hemorrhage, calcification, and fibrous tissue). In addition, they were stained with primary antibodies against CD68 (activated macrophages) and matrix metalloproteinase (MMP)-9. Results: High FDG uptake was detected in 13 (52.0%) of 25 patients. All of them had lipid-rich plaque. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to identify the lipid-rich plaques were all 100% for FDG-PET. More importantly, all of the FDG-positive plaques had strong immunoreactivity against both CD68 and MMP-9. There was a significant correlation between the findings on FDG-PET and those on immunohistochemistry against CD68 and MMP-9 (p = 0.006 and 0.004, respectively). On the other hand, 16 (64.0%) of 25 patients had high signal intensity plaque on BB-T1WI. In 7 of these 16 patients, the lesions also showed high signal intensity on TOF imaging. All of them had a large intraplaque hemorrhage. The sensitivity, specificity, PPV, and NPV to identify a large intraplaque hemorrhage were 70, 100, 100, and 83%, respectively, for MRI. Conclusions: These findings suggest that FDG-PET and MRI are complementary to predict high-risk carotid plaque, such as lipid-rich or hemorrhagic plaque. FDG-PET can accurately predict the lipid-rich and inflamed plaque. MRI is valuable to identify unstable plaque with a large intraplaque hemorrhage. The combination of these two modalities may play an important role in predicting carotid plaque at high risk of ischemic stroke.

123I-Iomazenil Single Photon Emission Computed Tomography Visualizes Recovery of Neuronal Integrity by Bone Marrow Stromal Cell Therapy in Rat Infarct Brain

Background and Purpose— This study was aimed to assess whether 123I-iomazenil (IMZ) single photon emission computed tomography can serially monitor the effects of bone marrow stromal cell (BMSC) transplantation on neuronal integrity in infarct brain of rats. Methods— The BMSCs were harvested from green fluorescent protein–transgenic rats and were cultured. The rats were subjected to permanent middle cerebral artery occlusion. Their motor function was serially quantified throughout the experiments. The BMSCs or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 days after the insult. Using small-animal single photon emission computed tomography/computed tomography apparatus, the 123I-IMZ uptake was serially measured at 6 and 35 days after the insult. Finally, fluorescence immunohistochemistry was performed to evaluate the distribution of engrafted cells and their phenotypes. Results— The distribution of 123I-IMZ was markedly decreased in the ipsilateral neocortex at 6 days postischemia. The vehicle-transplanted animals did not show a significant change at 35 days postischemia. However, BMSC transplantation significantly improved the distribution of 123I-IMZ in the peri-infarct neocortex as well as motor function. The engrafted BMSCs were densely distributed around cerebral infarct, and some of them expressed neuronal nuclear antigen and &ggr;-aminobutyric acid type-A receptor. Conclusions— The present findings strongly suggest that the BMSCs may enhance functional recovery by improving the neuronal integrity in the peri-infarct area, when directly transplanted into the infarct brain at clinically relevant timing. 123I-IMZ single photon emission computed tomography may be a promising modality to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situation.

18F-FDG-PET/CT better localizes active spinal infection than MRI for successful minimally invasive surgery

Background Surgical debridement is often required to treat spinal infections. Successful surgery requires accurate localization of the active infections, however, current imaging technique still requires surgeons’ experience to narrow the surgical fields to achieve less invasive procedures. Purpose To investigate the use of F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for successful surgical planning. Material and Methods Nine patients with suspected spinal infection underwent magnetic resonance imaging (MRI) and FDG-PET/CT before surgery to locate active foci of infections. The spinal structures were divided into seven compartments at each intervertebral disc level for a total of 315 compartments investigated. The same classification system was used to design operating fields for histological correlation. Results FDG-PET/CT diagnosed fewer compartments as active infection (34 compartments, 10.8%) than MRI (62 compartments, 19.7%, P  = 0.002). Surgical exploration was performed in 49 compartments, and demonstrated active infection in 25 compartments. The sensitivity / specificity of FDG-PET/CT was 100% / 79%, respectively, which was superior to those of MRI, 76% / 42%. Foci of active infection showed hypermetabolic activity with a SUVmax of 7.1 ± 2.6 (range, 3.0–12.7). Receiver operating characteristic (ROC) analysis indicated an optimal threshold for active spinal infection at a SUVmax of 4.2, corresponding to a sensitivity of 90.3% and specificity of 91.2%. Conclusion FDG-PET/CT demonstrated limited areas of abnormality allowing accurate delineation, and is thus useful to narrow the surgical fields. Since overall diagnostic accuracy of FDG-PET/CT was superior to that of MRI, FDG-PET/CT is a useful technique to narrow the surgical field for successful less invasive surgery.

Administration of unfractionated heparin with prolonged fasting could reduce physiological 18F-fluorodeoxyglucose uptake in the heart.

Background The physiological uptake of 18F-fluorodeoxyglucose (FDG) in the heart often interferes with the accurate diagnosis of inflammatory cardiac diseases (CDs). Unfractionated heparin (UFH) administration may suppress its uptake through the alteration of myocardial metabolism. Purpose To clarify the effectiveness of UFH administration to suppress the physiological FDG uptake in the heart. Material and Methods The physiological FDG uptake in the heart was compared among 178 patients who fasted less than 18 h, 37 patients who fasted more than 18 h, and 64 patients who fasted more than 18 h and were administered UFH (UFH-CD group) prior to FDG PET/CT. Free fatty acid (FFA), triglyceride, insulin, and blood glucose levels were measured after UFH administration. Myocardial FDG uptake was evaluated by visual assessment and on the basis of maximum standardized uptake value (SUVmax). Results In the UFH-CD group, the FFA level increased 15 min after UFH administration (P < 0.01). Blood glucose and insulin levels remained unchanged (P = NS). FDG physiological uptake was observed in 69% of the patients who fasted less than 18 h, 38% of the patients fasted more than 18 h, and 22% of the UFH-CD group (P < 0.01 for trend). SUVmax decreased in the UFH-CD group compared with the patients who fasted less than 18 h (P < 0.01) and the patients who fasted more than 18 h (P = 0.029). Conclusion UFH administration and fasting more than 18 h could effectively suppress FDG physiological uptake in the heart and can be a useful method of detecting inflammatory CDs and tumors.

Impaired myocardial sympathetic innervation is associated with diastolic dysfunction in heart failure with preserved ejection fraction: 11C-hydroxyephedrine PET study

Diastolic dysfunction is important in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Sympathetic nervous hyperactivity may contribute to the development of diastolic dysfunction. The aim of this study was to determine the relationship between myocardial sympathetic innervation quantified by 11C-hydroxyephedrine PET and diastolic dysfunction in HFpEF patients. Methods: Forty-one HFpEF patients having an echocardiographic left ventricular ejection fraction of 40% or greater and 12 age-matched volunteers without heart failure underwent the echocardiographic examination and 11C-hydroxyephedrine PET. Diastolic dysfunction was classified into grades 0–3 by Doppler echocardiography. Myocardial sympathetic innervation was quantified using the 11C-hydroxyephedrine retention index (RI). The coefficient of variation of 17-segment RIs was derived as a measure of heterogeneity in myocardial 11C-hydroxyephedrine uptake. Results: Grade 2–3 diastolic dysfunction (DD2–3) was found in 19 HFpEF patients (46%). They had a significantly lower global RI (0.075 ± 0.018 min−1) than volunteers (0.123 ± 0.028 min−1, P < 0.001) and HFpEF patients with grade 0–1 diastolic dysfunction (DD0–1) (0.092 ± 0.024 min−1, P = 0.046). HFpEF patients with DD2–3 had the largest coefficient of variation of 17-segment RIs of the 3 groups (18.4% ± 7.7% vs. 14.1% ± 4.7% in HFpEF patients with DD0–1, P = 0.042 for post hoc tests). In multivariate logistic regression analysis, a lower global RI (odds ratio, 0.66 per 0.01 min−1; 95% confidence interval, 0.38–0.99; P = 0.044) was independently associated with the presence of DD2–3 in HFpEF patients. Conclusion: Myocardial sympathetic innervation was impaired in HFpEF patients and was associated with the presence of advanced diastolic dysfunction in HFpEF.

Feasibility of Quantifying Myocardial Blood Flow with a Shorter Acquisition Time Using 15 O-H 2 O PET

Purpose: The quantification of coronary flow reserve (CFR) calculated as the ratio of the myocardial blood flow (MBF) during adenosine triphosphate (ATP) stress to MBF at rest is a useful method for evaluating the functional severity of coronary artery disease (CAD) using 15 O-H2O positron emission tomography (PET). The shorter acquisition time may reduce dyspnea and other side effects of ATP stress and may also reduce the effect of body movements during data acquisition. However, the impact of the shorter data acquisition time on the accuracy of MBF quantification has not been studied. In this retrospective study, we evaluated the accuracy of the MBF and CFR values obtained with shorter scan times using 15 O-H2O PET. Methods: Thirty patients suspected of having CAD (22 males, 8 females; age 56.5±8.8 yrs) and 17 healthy controls (17 males; age 27.7±6.2 yrs) underwent PET during rest and PET with ATP stress dynamic 15 O-H2O. The MBF was estimated with a one-tissue compartment model analysis. MBF and CFR values were calculated using the first 2-min and 3-min PET data of 15 O-H2O as shorter data acquisitions. These data were compared to the standard 6-min PET acquisition data. Results: With the use of the 3-min data, the regions of interest (ROIs) in the left ventricular (LV) chamber and myocardium could be set for all of the subjects. The intraclass correlation coefficients (ICCs) between the 3-min data and 6-min data of the rest MBF, stress MBF and CFR were 0.869, 0.870, and 0.819 in the patients, and 0.912, 0.910, and 0.930 in the controls. The 3-min CFR data showed a significant difference between the patients and controls (2.22±1.02 vs. 4.02±1.50, p<0.01), as did the 6-min data (2.19±0.92 vs. 4.16±1.39, p<0.01). However, the CFR based on 2-min data did not show a significant difference (1.96±1.66 vs. 2.73±1.03, p=0.088). Using a receiver operating characteristic (ROC) analysis, we observed that both the 3-min and 6-min CFR data could be used to separate the CAD patients and controls. Conclusions: A 3-min, but not 2-min, scan with 15 O-H2O PET can be used for the quantitative evaluation of MBF and CFR.

Effect of Attenuation Correction on Regional Quantification Between PET/MR and PET/CT: A Multicenter Study Using a 3-Dimensional Brain Phantom

A spatial bias in brain PET/MR exists compared with PET/CT, because of MR-based attenuation correction. We performed an evaluation among 4 institutions, 3 PET/MR systems, and 4 PET/CT systems using an anthropomorphic brain phantom, hypothesizing that the spatial bias would be minimized with CT-based attenuation correction (CTAC). Methods: The evaluation protocol was similar to the quantification of changes in neurologic PET studies. Regional analysis was conducted on 8 anatomic volumes of interest (VOIs) in gray matter on count-normalized, resolution-matched, coregistered data. On PET/MR systems, CTAC was applied as the reference method for attenuation correction. Results: With CTAC, visual and quantitative differences between PET/MR and PET/CT systems were minimized. Intersystem variation between institutions was +3.42% to −3.29% in all VOIs for PET/CT and +2.15% to −4.50% in all VOIs for PET/MR. PET/MR systems differed by +2.34% to −2.21%, +2.04% to −2.08%, and −1.77% to −5.37% when compared with a PET/CT system at each institution, and these differences were not significant (P ≥ 0.05). Conclusion: Visual and quantitative differences between PET/MR and PET/CT systems can be minimized by an accurate and standardized method of attenuation correction. If a method similar to CTAC can be implemented for brain PET/MRI, there is no reason why PET/MR should not perform as well as PET/CT.

Postoperative Assessment of Hepatic Asialoglycoprotein Receptor Function with Tc-99m GSA: The Safety Margin of Resection Size in Living Donor Liver Transplantation

BACKGROUND Living liver donation is associated with size-dependent complications. The resectable size and its safety margin should be defined for the safety of donors. The purpose of the present study was to determine if the current partial hepatectomies are done under the safety margin of the resectable size, by measuring asialoglycoprotein receptor (ASGPR) function of donors remnant liver. MATERIAL AND METHODS Seventy-four living donors (age 35±11 years) underwent Technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (Tc-99m GSA) scintigraphy at postoperative week 1. We evaluated the scintigraphic results using established parameters of GSA uptake (LHL15) and its clearance from the blood pool (HH15). Based on the literature, we consider HH15 <0.55 to indicate normal ASGPR function, and 0.55£ HH15 <0.65 to indicate mild impairment. In terms of the hepatic uptake, we consider LHL15>0.93 to indicate normal ASGPR function, and 0.87< LHL15 £0.93 to indicate mild impairment. RESULTS The average resected size was 337±170 mL, corresponding to 28±12% of the original donors whole liver volume. No donors showed 0.65≤ HH15 or LHL15 <0.87, suggesting moderate or severely impaired ASGPR function. However, larger resection size (35-53%) was positively associated with higher HH15 values (R=0.53, p<0.001). In the range of HH15 (0.35-0.64) among present donors, higher HH15 values did not affect the regeneration volume (R=0.03, p=NS). CONCLUSIONS Larger partial resection (≥35% of the original liver volume) may impair postsurgical ASGPR function, but smaller resection (<35%) was considered to be under the safety margin of the hepatectomy. Although mildly impaired postsurgical ASGPR function did not indicate poor prognosis, careful attention may be required for donors undergoing larger (³35%) partial resection.