Sadahiro Naka

Can Complementary 68Ga-DOTATATE and 18F-FDG PET/CT Establish the Missing Link Between Histopathology and Therapeutic Approach in Gastroenteropancreatic Neuroendocrine Tumors?

Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are indolent neoplasms presenting unpredictable and unusual biologic behavior that causes many clinical challenges. Tumor size, existence of metastasis, and histopathologic classification remain incapable in terms of treatment decision and prognosis estimation. This study aimed to compare 68Ga-DOTATATE and 18F-FDG PET/CT in GEPNETs and to investigate the relation between the complementary PET/CT results and histopathologic findings in the management of therapy, particularly in intermediate-grade patients. Methods: The relation between complementary 68Ga-DOTATATE and 18F-FDG PET/CT results of 27 GEPNET patients (mean age, 56 y; age range, 33–79 y) and histopathologic findings was evaluated according to grade and localization using standardized maximum uptake values and Ki67 indices. Grade 2 (G2) patients were further evaluated in 2 groups as G2a (3%–9%) and G2b (10%–20%) according to Ki67 indices. Results: The sensitivity of 68Ga-DOTATATE and 18F-FDG PET/CT was 95% and 37%, respectively, and the positive predictive values were 93.8% and 36.2%, respectively. The sensitivity in detecting liver metastasis, lymph nodes, bone metastasis, and primary lesion was 95%, 95%, 90%, and 93% for 68Ga-DOTATATE and 40%, 28%, 28%, and 75% for 18F-FDG, respectively. Statistically significant differences were found between grades 1–2, 2a–2b, and 1–2b with respect to 68Ga-DOTATATE PET/CT as well as between 1–2a and 1–2b with respect to 18F-FDG PET/CT. However, no statistical differences were found between 1 and 2a (P > 0.05) for 68Ga-DOTATATE and 2a and 2b (P = 0.484) for 18F-FDG. The impact of the combined 18F-FDG and 68Ga-DOTATATE PET/CT on the therapeutic decision was 59%. Conclusion: Combined 68Ga-DOTATATE and 18F-FDG PET/CT is helpful in the individual therapeutic approach of GEPNETs and can overcome the shortcomings of histopathologic grading especially in intermediate-grade GEPNETs.

Optimization of [11C]methionine PET study: appropriate scan timing and effect of plasma amino acid concentrations on the SUV

Background[11C]methionine (MET) has been used to monitor amino acid metabolism in tumors, the pancreas, liver, and myocardium. The aim of the present study was to standardize [11C]MET positron emission tomography (PET) by optimizing the timing of initiation of the scan and applying correction to the plasma concentrations of neutral amino acids (NAAs), where necessary.MethodsSequential whole-body MET PET/computed tomography (CT) was performed in 11 normal adults after they had fasted for at least 4 h. After whole-body CT for attenuation correction and intravenous bolus injection of MET, the subjects were scanned from the parietal to the groin. The scanning was repeated six to seven times. Decay of radioactivity during the PET scan was corrected to the time of initiation of the first scan. The standardized uptake values (SUVs) were evaluated in various organs by setting regions of interest on the tomographic images. Plasma concentrations of NAAs were examined in relation to the SUV values.ResultsThe SUVs in the pancreas reached their plateau from 6.5 to 11 min after the MET injection, and in the brain, lung, and myocardium, they reached their plateau from 19.6 to 24.1 min. The MET uptake in the spleen and kidney peaked early after the injection and steadily decreased thereafter. The SUVs in the liver and stomach wall rapidly increased during the first 0 to 4.5 min and gradually elevated thereafter during the scan period. Urinary radioactivity in the bladder reached its plateau from 26.1 to 30.6 min after the MET injection. There were no correlations between the plasma concentrations of NAAs and the maximal SUV in any organs.ConclusionsThe present study revealed the times taken to reach the plateau of MET uptake in various important organs, and little effects of the plasma neutral amino acid concentrations on the SUVs in PET studies conducted after the patients had fasted for at least 4 h. In the MET PET study, 4 h fasting period before MET administration and the scan initiation 20 min after MET administration provide the SUV values independent of scan initiation time and the plasma neutral amino acid concentrations.

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

Objective(s): 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.

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 Alzheimers 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 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. Methods The distribution of 11C-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 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-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 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-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 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.