Annals of Nuclear Medicine (v.30, #2)

Correlation of 4′-[methyl-11C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with 11C-methionine uptake by Kenichi Tanaka; Yuka Yamamoto; Yukito Maeda; Hiroyuki Yamamoto; Nobuyuki Kudomi; Nobuyuki Kawai; Jun Toyohara; Yoshihiro Nishiyama (89-96).
A novel radiopharmaceutical, 4′-[methyl-11C]thiothymidine (11C-4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate 11C-4DST uptake in patients with newly diagnosed glioma and to correlate the results with proliferative activity and tumor grade, in comparison with l-[methyl-11C]-methionine (11C-MET). Investigations of 11C-4DST and 11C-MET PET/CT were performed retrospectively in 23 patients with newly diagnosed glioma. The maximum standardized uptake value (SUVmax) for tumor (T) and the mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) was defined as the volume with a threshold of 40 % of the SUVmax. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens.Of 23 gliomas examined, 11C-4DST PET/CT and 11C-MET PET/CT detected 20 and 22, respectively. Linear regression analysis between 11C-4DST and 11C-MET indicated a weak correlation for SUVmax (r = 0.54, P < 0.008), for T/N ratio (r = 0.56, P < 0.006), and for MTV (r = 0.60, P < 0.003). Linear regression analysis indicated a weak correlation between 11C-4DST and Ki-67 index for SUVmax (r = 0.46, P < 0.03), for T/N ratio (r = 0.43, P < 0.05), and for MTV (r = 0.68, P < 0.001) and between 11C-MET MTV and Ki-67 index (r = 0.43, P < 0.04). Using 11C-4DST, there was a significant difference in SUVmax between grades II and IV (P < 0.03) and in MTV between grades II and IV (P < 0.009) and grades III and IV (P < 0.02). Using 11C-MET, there was a significant difference in SUVmax (P < 0.009) and T/N ratio (P < 0.02) between grades II and IV and in MTV between grades II and IV (P < 0.03) and grades III and IV (P < 0.02). 11C-4DST PET/CT is feasible for imaging of brain gliomas, as well as 11C-MET PET/CT. Especially, it showed the highest correlation coefficient between 11C-4DST MTV and Ki-67 index in newly diagnosed gliomas.
Keywords: 11C-4DST; 11C-MET; PET; Glioma; Proliferation

The edge artifact in the point-spread function-based PET reconstruction at different sphere-to-background ratios of radioactivity by Daisuke Kidera; Ken Kihara; Go Akamatsu; Shohei Mikasa; Takafumi Taniguchi; Yuji Tsutsui; Toshiki Takeshita; Akira Maebatake; Kenta Miwa; Masayuki Sasaki (97-103).
The aim of this study was to quantitatively evaluate the edge artifacts in PET images reconstructed using the point-spread function (PSF) algorithm at different sphere-to-background ratios of radioactivity (SBRs).We used a NEMA IEC body phantom consisting of six spheres with 37, 28, 22, 17, 13 and 10 mm in inner diameter. The background was filled with 18F solution with a radioactivity concentration of 2.65 kBq/mL. We prepared three sets of phantoms with SBRs of 16, 8, 4 and 2. The PET data were acquired for 20 min using a Biograph mCT scanner. The images were reconstructed with the baseline ordered subsets expectation maximization (OSEM) algorithm, and with the OSEM + PSF correction model (PSF). For the image reconstruction, the number of iterations ranged from one to 10. The phantom PET image analyses were performed by a visual assessment of the PET images and profiles, a contrast recovery coefficient (CRC), which is the ratio of SBR in the images to the true SBR, and the percent change in the maximum count between the OSEM and PSF images (Δ % counts).In the PSF images, the spheres with a diameter of 17 mm or larger were surrounded by a dense edge in comparison with the OSEM images. In the spheres with a diameter of 22 mm or smaller, an overshoot appeared in the center of the spheres as a sharp peak in the PSF images in low SBR. These edge artifacts were clearly observed in relation to the increase of the SBR. The overestimation of the CRC was observed in 13 mm spheres in the PSF images. In the spheres with a diameter of 17 mm or smaller, the Δ % counts increased with an increasing SBR. The Δ % counts increased to 91 % in the 10-mm sphere at the SBR of 16.The edge artifacts in the PET images reconstructed using the PSF algorithm increased with an increasing SBR. In the small spheres, the edge artifact was observed as a sharp peak at the center of spheres and could result in overestimation.
Keywords: Edge artifact; Point-spread function; PET

Comparison of FDG PET/CT and MRI in lymph node staging of endometrial cancer by Hyun Jeong Kim; Arthur Cho; Mijin Yun; Young Tae Kim; Won Jun Kang (104-113).
Endometrial cancer is the most frequent cancer occurring in the female genital tract in the Western countries. Because surgical staging is currently the standard, noninvasive techniques that accurately identify lymph node (LN) metastases would be beneficial by reducing costs and complications. The purpose of our study is to compare the diagnostic accuracy of 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) with that of magnetic resonance imaging (MRI) for detecting LN metastases in the preoperative staging of endometrial cancer.Two hundred eighty-seven consecutive patients with endometrial cancer underwent preoperative PET/CT and MRI for staging. The malignancy criteria for LNs were a short diameter of 1 cm or more by MRI and focally increased 18F-FDG uptake by PET/CT. After evaluating PET/CT and MRI separately, morphologic and functional image findings were compared with the histological findings regarding LN metastasis for all patients. PET/CT and MRI images were classified on the basis of histological findings as true-positive, true-negative, false-positive, or false-negative. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated.Histologic examination revealed LN metastases in 51 patients (17.8 %). The maximal standardized uptake values (SUVmax) of the primary lesions by PET/CT ranged from 1.4 to 37.7, with a mean value of 9.3, whereas those of the metastatic LNs ranged from 2.0 to 22.5 with a mean of 7.3. On a per-patient basis, node staging resulted in sensitivities of 70.0 % with 18F-FDG PET/CT and 34.0 % with MRI, and specificities of 95.4 % with PET/CT and 95.0 % with MRI. The NPV of PET/CT was 94.3 %, and that of MRI was 87.2 %. On a lesion base analysis, sensitivity of PET/CT was 79.4 % while that of MRI was 51.6 %. In detecting distant metastasis, the sensitivity, specificity, accuracy, PPV, and NPV of PET/CT were 92.9, 98.9, 98.6, 81.3, and 99.6 %, respectively.Diagnostic performance of FDG PET/CT was better than MRI for detecting metastatic lymph nodes in patients with endometrial cancer both by patient basis and lesion basis analyses. Due to high NPV, FDG PET-CT could aid in selecting candidates for lymphadenectomy.
Keywords: Endometrial cancer; Staging; 18F-fluoro-2-deoxy-d-glucose positron emission tomography; Lymph node

FDG PET/CT for assessing the resectability of NSCLC patients with N2 disease after neoadjuvant therapy by Ran Kremer; Yury Peysakhovich; Levy-Faber Dan; Ludmila Guralnik; Olga Kagna; Rony-Reuven Nir; Rachel Bar-Shalom (114-121).
Neoadjuvant chemoradiotherapy (CMRT) is the most effective treatment of stage III non-small-cell lung cancer (NSCLC). The present study aimed at assessing FDG PET/CT for defining the response of N2 disease to neoadjuvant CMRT, as surgical resection after such therapy significantly improves 5-year survival in responding N2 disease.Forty-five patients with locally advanced NSCLC underwent both pre-neoadjuvant therapy FDG PET/CT and post-neoadjuvant therapy FDG PET/CT followed by anatomical resection of lung and ipsilateral mediastinal lymph nodes (LN). Seventeen of these patients who had PET/CT studies in our institution and were operated after CMRT were retrospectively included in the study group (12 males, ages 43–78 years; stage IIIA: 14 patients, stage IIIB: 3 patients). PET/CT response in N2 was visually scored per-lymph node station and per patient. Quantitative N2 response was evaluated by SUVmax and total lesion glycolysis (TLG) measurements after therapy alone and in comparison with pre-therapy values. PET/CT N2 response was confirmed at surgery.Seventeen NSCLC patients with 29 metastatic N2 lymph nodes (LN) were assessed. Histopathology confirmed 14 responders and 3 non-responders, and was available in 20/29 metastatic LN, showing complete response in 17 and residual disease in 3 LN. LN-based visual analysis of N2 response on PET/CT defined 3 TP, 16 TN and 1 FP, for sensitivity, specificity, accuracy, negative and positive predictive values (NPV and PPV) of 100, 94, 95, 100 and 75 %, respectively. Patient-based visual analysis defined 3 TP, 13 TN and 1 FP study, for sensitivity, specificity, accuracy, NPV and PPV of 100, 93, 94, 100 and 75 %, respectively. Nodal-based quantitative analysis of FDG uptake in N2 nodes revealed a significant difference between responding and non-responding LN only of SUVmax post-therapy (2.5 ± 1.21 vs. 3.5 ± 2.36, P = 0.04).FDG PET/CT after neoadjuvant therapy accurately defined response in metastatic N2 nodes of NSCLC patients, presenting very high sensitivity and NPV for detecting responding nodes. PET/CT may enable selection of candidates for curative resection of stage III NSCLC. Mediastinoscopy may not be mandatory in patients with a negative PET/CT after neoadjuvant therapy.
Keywords: NSCLC; N2 disease; FDG PET/CT; Neoadjuvant therapy; Resectability

Synthesis and evaluation of a new vesamicol analog o-[11C]methyl-trans-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter by Yoji Kitamura; Takashi Kozaka; Daisuke Miwa; Izumi Uno; Mohammad Anwar-ul Azim; Kazuma Ogawa; Junichi Taki; Seigo Kinuya; Kazuhiro Shiba (122-129).
We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer’s diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [11C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation.[11C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [11C]methyl iodide, with a radiochemical yield of 60–75 %, a radiochemical purity of greater than 98 %, and a specific activity of 5–10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [11C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET–CT imaging study were performed to check the binding selectivity of [11C]OMDV for VAChT.In vivo studies demonstrated [11C]OMDV passage through the blood–brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [11C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [11C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET–CT imaging revealed inhibition of [11C]OMDV accumulation in the brain by co-administration of vesamicol.[11C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [11C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.
Keywords: PET; Vesamicol analogs; Vesicular acetylcholine transporter; Presynaptic cholinergic neurons

A preliminary report of breast cancer screening by positron emission mammography by Yayoi Yamamoto; Youichiro Tasaki; Yukiko Kuwada; Yukihiko Ozawa; Tomio Inoue (130-137).
Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET/computed tomography (PET/CT) have had a considerable impact on the detection of various malignancies. PET and PET/CT are minimally invasive methods that can provide whole-body imaging at one time. Therefore, an FDG-PET cancer screening program has been widely used in Japan. However, the breast cancer detection rate of FDG-PET cancer screening is relatively low. Therefore, FDG-PET screening is not recommended for breast cancer screening. Positron emission mammography (PEM) is a high-resolution molecular breast imaging technology. PEM can detect small breast cancers that cannot be detected on PET or PET/CT images due to limited spatial resolution. We have performed opportunistic breast cancer screening using PEM since 2011. To the best of our knowledge, this is the first report regarding PEM breast cancer screening.This study enrolled 265 women. PEM images were analyzed by agreement of 2 experienced nuclear medicine physicians. The readers were given information from medical interview sheet. US findings were interpreted holistically. The number of participants, patient recall rate, further examination rate, and cancer detection rate by year were calculated.The overall recall rate was 8.3 %; the work-up examination rate was 77.3 %, and cancer detection rate was 2.3 %. The positive predictive value of PEM was 27.3 %. Six cancers were found by PEM screening. Five were invasive cancers and one was ductal carcinoma in situ. Histological tumor sizes were reported in three cases: 0.7, 1.2, and 2 cm.PEM screening appears to have potential for breast cancer screening.
Keywords: Positron emission mammography; Breast cancer screening; FDG-PET screening

The common form and risk factors of electrocardiogram (ECG) abnormality in thyroidectomized differentiated thyroid carcinoma (DTC) patients with short-term overt hypothyroidism were investigated and some discriminant formulas for forecasting the occurrence of abnormal ECG in this specific population were deduced in this study.A total of 260 thyroidectomized DTC patients were retrospectively reviewed, 67 of whom had abnormal ECG and 193 normal ECG after short-term (3 weeks) levothyroxine (L-T4) withdrawal. One-way ANOVA, Spearman’s rank correlation analysis and discriminant function analysis were performed using data from these DTC patients.A flat or inverted T wave in inferior myocardial and left ventricular wall leads was the most common abnormal ECG finding in short-term overt hypothyroidism. Statistical analyses showed that age, interval, TSH-end (The serum hormothyrin level at the end of L-T4 withdrawal for 3 weeks), and TSH-vel (The average ascending velocity of serum hormothyrin level during L-T4 withdrawal for 3 weeks) were statistically significant and positively correlated with the occurrence of abnormal ECG. Meanwhile, TSH-vel showed the highest correlation coefficient (r = 0.358, p = 0.000). The formulas, especially deduced from age, interval and TSH-vel, could discriminate patients with abnormal ECG or not as high as 77.6 and 70.5 %, respectively (resubstitution accuracy: 72.3 %).The thyroidectomized DTC patients undergoing short-term L-T4 withdrawal before their first radioiodine ablative therapy, who had one or more of the above-mentioned risk factors, are likely to show abnormal ECG findings. The formulas from discriminant function analysis may be helpful for predicting patients with abnormal ECG with short-term L-T4 withdrawal and allow appropriate medical intervention beforehand.
Keywords: Short-term overt hypothyroidism; Electrocardiogram; Differentiated thyroid carcinoma; Discriminant analysis

Current generation time-of-flight 18F-FDG PET/CT provides higher SUVs for normal adrenal glands, while maintaining an accurate characterization of benign and malignant glands by Daniëlle Koopman; Jorn A. van Dalen; Jos A. Stigt; Cornelis H. Slump; Siert Knollema; Pieter L. Jager (145-152).
Modern PET/CT scanners have significantly improved detectors and fast time-of-flight (TOF) performance and this may improve clinical performance. The aim of this study was to analyze the impact of a current generation TOF PET/CT scanner on standardized uptake values (SUV), lesion-background contrast and characterization of the adrenal glands in patients with suspected lung cancer, in comparison with literature data and commonly used SUV cut-off levels.We included 149 adrenal glands from 88 patients with suspected lung cancer, who underwent 18F-FDG PET/CT. We measured the SUVmax in the adrenal gland and compared this with liver SUVmean to calculate the adrenal-to-liver ratio (AL ratio). Results were compared with literature derived with older scanners, with SUVmax values of 1.0 and 1.8 for normal glands [1, 2]. Final diagnosis was based on histological proof or follow-up imaging. We proposed cut-off values for optimal separation of benign from malignant glands.In 127 benign and 22 malignant adrenal glands, SUVmax values were 2.3 ± 0.7 (mean ± SD) and 7.8 ± 3.2 respectively (p < 0.01). Corresponding AL ratios were 1.0 ± 0.3 and 3.5 ± 1.4 respectively (p < 0.01). With a SUVmax cut-off value of 3.7, 96 % sensitivity and 96 % specificity was reached. An AL ratio cut-off value of 1.8 resulted in 91 % sensitivity and 97 % specificity. The ability of both SUVmax and AL ratio to separate benign from malignant glands was similar (AUC 0.989 vs. 0.993, p = 0.22).Compared with literature based on the previous generation of PET scanners, current generation TOF 18F-FDG PET/CT imaging provides higher SUVs for benign adrenal glands, while it maintains a highly accurate distinction between benign and malignant glands. Clinical implementation of current generation TOF PET/CT requires not only the use of higher cut-off levels but also visual adaptation by PET readers.
Keywords: 18F-FDG; PET/CT; Adrenal glands; Lung cancer

Evaluation of 99mTc-TRODAT-1 SPECT in the diagnosis of Parkinson’s disease versus other progressive movement disorders by Babak Fallahi; Atefe Esmaeili; Davood Beiki; Shahram Oveisgharan; Hamid Noorollahi-Moghaddam; Mostafa Erfani; Abbas Tafakhori; Mohammad Rohani; Armaghan Fard-Esfahani; Alireza Emami-Ardekani; Parham Geramifar; Mohammad Eftekhari (153-162).
Parkinson disease (PD), parkinsonian syndromes (PS) and essential tremor (ET) are different types of movement disorders which share some symptoms resulting in a difficulty of certain diagnosis. This study was conducted to determine the value of 99mTc-TRODAT-1 scan to differentiate PD from ET and other PS cases.Totally, 75 patients were studied including 29 PD, 6 possible PD, 22 ET and 18 PS cases. A dual-head SPECT-CT was used to perform basal ganglia (BG) imaging following administration of 99mTc-TRODAT-1. The BG uptake values were normalized to whole brain and occipital activity. All patients were followed for 2–22 months to reach a certain diagnosis.Patients with ET and drug-induced parkinsonism show significantly higher normalized BG uptake as compared to the other subgroups; however, no significant difference was noted between PD and PS patients. The sensitivity and specificity of the findings for the differentiation between patients with the disease associated versus not associated with BG dysfunction were 80 and 83.3 %, respectively. A predictive positive value of 82.6 % was obtained using an additive scaling index defined as asymmetry and unevenness of uptake in putamen and/or caudate contralateral to the dominant side of current symptoms. 99mTc-TRODAT-1 scan is an appropriate method to differentiate PD or PS versus ET. A combination of scan pattern including asymmetry of BG uptake and unevenness of activity in caudate and putamen along with the side of dominant symptoms may be valuable for the differentiation of Parkinson’s disease from the other parkinsonian syndromes.
Keywords: 99mTc-TRODAT-1; Parkinson’s disease; Parkinsonian syndrome; Essential tremor; SPECT

A case report of image-based dosimetry of bone metastases with Alpharadin (223Ra-dichloride) therapy: inter-fraction variability of absorbed dose and follow-up by Massimiliano Pacilio; Guido Ventroni; Bartolomeo Cassano; Pasquale Ialongo; Leda Lorenzon; Elisabetta Di Castro; Federica Recine; Cora N. Sternberg; Lucio Mango (163-168).
A 70-year-old man affected by bone metastases from castration resistant prostate cancer underwent Alpharadin (223Ra-dichloride) therapy (6 administrations of 50 kBq per kg i.v., once every 4 weeks). The inter-fraction variability of the absorbed dose to lesions was evaluated for four injections. Dosimetric assessments were performed following the MIRD approach and a recently published methodology. The mean absorbed dose and standard deviation for 4 lesions [mean (σ %)] were: 434 mGy (15 %) and 516 mGy (21 %) for the right and left humeral head, 1205 mGy (14 %) and 781 mGy (8 %) for the right and left glenoid. The estimated total absorbed dose after the whole treatment, considering also the relative-biological effectiveness of alpha particles (RBE = 5), yielded a D RBE range of 13–36 Gy. A good correlation between 99mTc and 223Ra uptake was obtained (R 2 = 0.7613). The tumour–non-tumour (TNT) ratio of 8 lesions (those above, plus 4 additional), monitored by six 99mTc-MDP bone scans over a period of about 10 months, evidenced a TNT reduction in two lesions (−42 and −48 %), but in most lesions the TNT remained fairly constant, evidencing that 223Ra-dichloride therapy tends to prevent further progression of osseous disease, leading to chronicity of the metastatic status.
Keywords: Bone metastases; 223Ra-dichloride; Radionuclide therapy; Dosimetry

Iodine-131 imaging using 284 keV photons with a small animal CZT-SPECT system dedicated to low-medium-energy photon detection by Akihiro Kojima; Kumiko Gotoh; Masako Shimamoto; Koki Hasegawa; Seiji Okada (169-175).
Iodine-131 is widely used for radionuclide therapy because of its β-particle and for diagnostic imaging employing its principal gamma ray. Since that principal gamma ray has the relatively high energy of 364 keV, small animal single-photon emission computed tomography (SPECT) imaging systems may be required to possess the ability to image such higher energy photons. The aim of this study was to investigate the possibility of imaging I-131 using its 284 keV photons instead of its 364 keV photons in a small animal SPECT imaging system dedicated to the detection of low-medium-energy photons (below 300 keV).The imaging system used was a commercially available preclinical SPECT instrument with CZT detectors that was equipped with multi-pinhole collimators and was accompanied by a CT imager. An energy window for I-131 imaging was set to a photopeak of 284 keV with a low abundance compared with 364 keV photons. Small line sources and two mice, one of each of two types, that were injected with NaI-131 were scanned.Although higher counts occurred at the peripheral region of the reconstructed images due to the collimator penetration by the 364 keV photons, the shape of the small line sources could be well visualized. The measured spatial resolution was relatively poor (~1.9 mm for full width at half maximum and ~3.9 mm for full width at tenth maximum). However, a good linear correlation between SPECT values and the level of I-131 radioactivity was observed. Furthermore, the uptake of NaI-131 to the thyroid gland for the two mice was clearly identified in the 3D-SPECT image fused with the X-ray CT image.We conclude that the use of an energy window set on the photopeak of 284 keV and the multi-pinhole collimator may permit I-131 imaging for a preclinical CZT-SPECT system that does not have the ability to acquire images using the 364 keV photons.
Keywords: A small animal CZT-SPECT system; Iodine-131 imaging; 284 keV photons