Annals of Nuclear Medicine (v.31, #8)

Topics of nuclear medicine research in Europe by Masayuki Inubushi; Tomohiro Kaneta; Takayoshi Ishimori; Etsuko Imabayashi; Atsutaka Okizaki; Naohiko Oku (571-574).
Last year in the European Journal of Nuclear Medicine and Molecular Imaging, we introduced some recent nuclear medicine research conducted in Japan. This was favorably received by European readers in the main. This year we wish to focus on the Annals of Nuclear Medicine on some of the fine nuclear medicine research work executed in Europe recently. In the current review article, we take up five topics: prostate-specific membrane antigen imaging, recent advances in radionuclide therapy, [18F]fluorodeoxyglucose positron-emission tomography (PET) for dementia, quantitative PET assessment of myocardial perfusion, and iodine-124 (124I). Just at the most recent annual meeting of the European Association of Nuclear Medicine 2016, Kyoto was selected as the host city for the 2022 Congress of the World Federation of Nuclear Medicine and Biology. We hope that our continuous efforts to strengthen scientific cooperation between Europe and Japan will bring many European friends and a great success to the Kyoto meeting.
Keywords: Prostate-specific membrane antigen (PSMA); Radionuclide therapy; Dementia; Quantitative myocardial perfusion PET; Iodine-124 (124I)

Fluorodeoxyglucose-positron emission tomography/computed tomography performs better than contrast-enhanced computed tomography for metastasis evaluation in the initial staging of pancreatic adenocarcinoma by Sampath Santhosh; Bhagwant Rai Mittal; Deepak Kumar Bhasin; Surinder Singh Rana; Rajesh Gupta; Ashim Das; Ritambhra Nada (575-581).
To evaluate the additional role of FDG-PET/CT to the conventional multiphasic CECT in the initial staging of pancreatic adenocarcinoma.54 patients diagnosed with pathologically proven pancreatic malignancy underwent FDG-PET/CECT. The sensitivity, specificity, PPV, NPV, and accuracy of PET/CT and CECT for nodal and metastatic staging were calculated. The statistical difference was calculated by McNemar’s test.Of 54 patients, 15 had distal metastasis. The sensitivity, specificity, PPV, NPV, and accuracy of PET/CT and CECT for nodal staging were 33 vs 89%, 84 vs 100%, 67 vs 100%, 60 vs 90%, and 59 vs 95%, respectively, p < 0.001. The sensitivity, specificity, PPV, NPV, and accuracy of CECT for metastatic staging were 73, 87, 69, 89, and 83%, whereas the accuracy of PET/CT was 100%, p = 0.01. By correctly characterizing unsuspected distant lesions, PET/CT could change management in 19% of patients.FDG-PET/CT can contribute to change in the management in almost one of every five patients of PA evaluated with the standard investigations during the initial staging.
Keywords: FDG-PET/CECT; Pancreatic adenocarcinoma; Staging; Metastasis; Malignancy

I-131 biokinetics of remnant normal thyroid tissue and residual thyroid cancer in patients with differentiated thyroid cancer: comparison between recombinant human TSH administration and thyroid hormone withdrawal by Chae Moon Hong; Choon-Young Kim; Seung Hyun Son; Ji-hoon Jung; Chang-Hee Lee; Ju Hye Jeong; Shin Young Jeong; Sang-Woo Lee; Jaetae Lee; Byeong-Cheol Ahn (582-589).
The aim of this study was to assess I-131 biokinetics in thyroid cancer and remnant tissue in patients with differentiated thyroid cancer using whole-body scan (WBS) and SPECT images acquired after I-131 therapy. The influence of thyroid stimulating hormone (TSH) stimulation method on the kinetics was also evaluated.A total of 57 patients who received I-131 therapy (2.96–7.4 GBq) were retrospectively included. TSH stimulation was achieved by recombinant human thyrotropin (rhTSH) or by thyroid hormone withdrawal (THW). Each patient received three sequential WBSs on days 1, 2, and 4 (or 5) after I-131 administration. All lesions were classified either as thyroid remnant (ThyR) or as metastatic lymph nodes (mLN) after considering the SPECT/CT images acquired during the last WBS. The lesion-based retention rate and absorbed dose of ThyR and mLN were calculated using a commercial dosimetric toolkit combined with the OLINDA software.The retention rate and the effective half-time of mLN were lower than that of ThyR (p < 0.001, p = 0.003). In addition, the retention rate and the effective half-time of ThyR in the rhTSH group were higher than those in the THW group (p < 0.001, p < 0.001). The differences in the retention rate and the effective half-time of mLN were not statistically significant between the THW group and rhTSH group (p = 0.549, p = 0.571).Radioiodine therapy using rhTSH delivered an at least similar radiation dose to target lesions compared to using THW in thyroid remnants and metastatic lymph nodes.
Keywords: I-131; Biokinetics; TSH stimulation; Retention rate; Effective half-time; rhTSH

High FDG uptake on PET is associated with negative cell-to-cell adhesion molecule E-cadherin expression in lung adenocarcinoma by Kotaro Higashi; Yoshimichi Ueda; Miyako Shimasaki; Yasuhito Ishigaki; Yuka Nakamura; Manabu Oguchi; Tsutomu Takegami; Naoto Watanabe (590-595).
E-cadherin is a main cell-to-cell adhesion molecule. A negative expression of E-cadherin correlates with distant metastasis in lung cancer. Recently, it was reported that there is an association between FDG uptake on PET and epithelial-mesenchymal transition (EMT) in non-small cell lung cancer. Downregulation of E-cadherin is one of the best markers of EMT. The purpose of this study was to compare E-cadherin expression with FDG uptake on PET, cell differentiation, aggressiveness and post-operative recurrence in patients with lung adenocarcinoma, and to investigate whether FDG uptake on PET is associated with E-cadherin expression.We retrospectively reviewed 40 lung adenocarcinoma patients who underwent thoracotomy and FDG PET before thoracotomy. These patients were evaluated FDG PET metrics such as standardized uptake value (SUV), the immunohistochemical expression of E-cadherin in surgical specimens, clinicopathological features, including tumor size, pathologic stage, cell differentiation, aggressiveness and post-operative recurrence.High FDG uptake correlated with negative E-cadherin expression (P = 0.043). SUVmax was higher in a negative E-cadherin expression lung adenocarcinoma than in a positive E-cadherin expression lung adenocarcinoma (P = 0.033). Patients with moderately poorly differentiated adenocarcinoma had frequent negative E-cadherin expression or high FDG uptake (P = 0.004, P = 0.0001, respectively). Patients with aggressive adenocarcinoma had frequent negative E-cadherin expression or high FDG uptake (P = 0.004, P = 0.001, respectively). Kaplan–Meier analysis revealed that negative E-cadherin expression or high FDG uptake were strongly correlated with shortened disease-free survival (P = 0.0153, P = 0.0001, respectively).High FDG uptake on PET was associated with negative E-cadherin expression in patients with lung adenocarcinoma. Both high FDG uptake and negative E-cadherin expression were strongly correlated with poor differentiation, aggressiveness, and post-operative recurrence. These findings may cause the association between high FDG uptake and negative E-cadherin expression.
Keywords: PET; FDG; Lung adenocarcinoma; E-cadherin; Recurrence

FMISO accumulation in tumor is dependent on glutathione conjugation capacity in addition to hypoxic state by Yukiko Masaki; Yoichi Shimizu; Takeshi Yoshioka; Ken-ichi Nishijima; Songji Zhao; Kenichi Higashino; Yoshito Numata; Nagara Tamaki; Yuji Kuge (596-604).
18F-fluoromisonidazole (FMISO), a well-known PET imaging probe for diagnosis of hypoxia, is believed to accumulate in hypoxic cells via covalent binding with macromolecules after reduction of the nitro group. Previously, we showed the majority of 18F-FMISO was incorporated into low-molecular-weight metabolites in hypoxic tumors, and the glutathione conjugate of reduced FMISO (amino-FMISO-GS) distributed in the tumor hypoxic regions as revealed by imaging mass spectrometry (IMS). The present study was conducted to clarify whether FMISO is metabolized to amino-FMISO-GS within tumor cells and how amino-FMISO-GS contributes to FMISO accumulation in hypoxic cells. We also evaluated the relationship between FMISO accumulation and the glutathione conjugation-related factors in the cells.Tumor cells (FaDu, LOVO, and T24) were treated with 18F-FMISO and incubated under normoxic or hypoxic conditions for 4 h. The FMISO metabolites were analyzed with LC–ESI–MS. Several glutathione conjugation-related factors of tumor cells were evaluated in vitro. FaDu tumor-bearing mice were intravenously injected with 18F-FMISO and the tumors were excised at 4 h post-injection. Autoradiography, IMS and histologic studies were performed.Amino-FMISO-GS was the main contributor to FMISO incorporated in hypoxic FaDu cells in vitro and in vivo. Total FMISO uptake levels and amino-FMISO-GS levels were highest in FaDu, followed by LOVO, and then T24 (total uptake: 0.851 ± 0.009 (FaDu), 0.617 ± 0.021 (LOVO) and 0.167 ± 0.006 (T24) % dose/mg protein; amino-FMISO-GS: 0.502 ± 0.035 (FaDu), 0.158 ± 0.013 (LOVO), and 0.007 ± 0.001 (T24) % dose/mg protein). The glutathione level of FaDu was significantly higher than those of LOVO and T24. The enzyme activity of glutathione-S-transferase catalyzing the glutathione conjugation reaction in FaDu was similar levels to that in LOVO, and was higher than that in T24. Quantitative RT-PCR analysis revealed that the expression levels of efflux transporters of the glutathione conjugate (multidrug resistance-associated protein 1) were lowest in FaDu, followed by LOVO, and then T24.FMISO accumulates in hypoxic cells through reductive metabolism followed by glutathione conjugation. We illustrated the possibility that increased production and decreased excretion of amino-FMISO-GS contribute to FMISO accumulation in tumor cells under hypoxic conditions.
Keywords: FMISO; Glutathione; Hypoxia; Imaging mass spectrometry; Molecular imaging

Cross calibration of 123I-meta-iodobenzylguanidine heart-to-mediastinum ratio with D-SPECT planogram and Anger camera by Kenichi Nakajima; Koichi Okuda; Kunihiko Yokoyama; Tatsuya Yoneyama; Shiro Tsuji; Hiroyuki Oda; Mitsuhiro Yoshita; Koji Kubota (605-615).
Cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake is quantified using the heart-to-mediastinum ratio (HMR) with an Anger camera. The relationship between HMR determined using D-SPECT with a cadmium–zinc–telluride detector and an Anger camera is not fully understood. Therefore, the present study aimed to define this relationship using images derived from a phantom and from patients.Cross-calibration phantom studies using an Anger camera with a low-energy high-resolution (LEHR) collimator and D-SPECT, and clinical 123I-MIBG studies proceeded in 40 consecutive patients (80 studies). In the phantom study, a conversion coefficient (CC) was defined based on phantom experiments and applied to the Anger camera and the D-SPECT detector. The HMR was calculated using anterior images with the Anger camera and anterior planograms with D-SPECT. First, the HMR from D-SPECT was cross-calibrated to the Anger camera, and then, the HMR from both cameras were converted to the medium-energy general-purpose collimator condition (CC 0.88; ME88 condition). The relationship between HMR and corrected and uncorrected methods was examined. A 123I-MIBG washout rate was calculated using both methods with and without background subtraction.Based on the phantom experiments, the CC of the Anger camera with an LEHR collimator and of D-SPECT using an anterior planogram was 0.55 and 0.63, respectively. The original HMR from the Anger camera and D-SPECT was 1.76 ± 0.42 and 1.86 ± 0.55, respectively (p < 0.0001). After D-SPECT HMR was converted to the Anger camera condition, the corrected D-SPECT HMR became comparable to the values under the Anger camera condition (1.75 ± 0.48, p = n. s.). When the HMR measured using the two cameras were converted under the ME88 condition, the average standardized HMR from the Anger camera and D-SPECT became comparable (2.21 ± 0.65 vs. 2.20 ± 0.75, p = n. s.). After standardization to the ME88 condition, a systematic difference in the linear regression lines disappeared, and the HMR from both the Anger (StdHMRAnger) and D-SPECT (StdHMRDSPECT) became comparable. Additional correction using a regression line further improved the relationship between both HMR [StdHMRDSPECT = 0.09 + 0.98 × StdHMRAnger (R 2 = 0.91)]. The washout rate closely correlated with and without background correction between both methods (R 2 = 0.83 and 0.65, respectively).The phantom-based conversion method is applicable to D-SPECT and enables the common application of HMR irrespective of D-SPECT and the Anger camera.
Keywords: Heart-to-mediastinum ratio; Quantitation; Standardization; Sympathetic imaging; Conversion coefficient

Early stimulated thyroglobulin for response prediction after recombinant human thyrotropin-aided radioiodine therapy by Hee Jeong Park; Jung-Joon Min; Hee-Seung Bom; Jahae Kim; Ho-Chun Song; Seong Young Kwon (616-622).
Measurement of recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin (Tg) is generally recommended 72 h after the second rhTSH injection. However, due to the acute effect of I-131 on thyrocytes, Tg measured after radioiodine therapy (RIT) would not accurately reflect the thyroid tissue burden. We aimed to determine predictive values of serum Tg level measured just before rhTSH-aided RIT and to compare the results obtained just after RIT in patients with differentiated thyroid carcinoma (DTC).We evaluated 150 patients with DTC who underwent rhTSH-aided RIT (2.96–6.66 GBq) after total thyroidectomy between 2009 and 2014. Serum Tg level was measured 24 h (early Tg) and 72 (or 96) h (delayed Tg) after the second rhTSH injection. An excellent response was defined based on the latest American Thyroid Association Guidelines. Univariate and multivariate analyses were performed for early Tg, delayed Tg, and other clinical variables.In the multivariate analysis, tumor size [odds ratio (OR) 1.716; 95% confidence interval (CI) 1.019–2.882; p = 0.042] and early Tg level (OR 2.012; 95% CI 1.384–2.925, p < 0.001) independently predicted excellent responses. The cutoff for the best early Tg level to predict a non-excellent response was 2.0 ng/mL. Delayed Tg was not a significant predictor (OR 0.992; 95% CI 0.969–1.015; p = 0.492).Early stimulated Tg significantly predicted therapeutic response after rhTSH-aided RIT in patients with DTC. Therefore, serum Tg should be measured before RIT to predict therapeutic responses.
Keywords: Differentiated thyroid carcinoma; Radioiodine therapy; Recombinant human thyrotropin; Thyroglobulin; Therapeutic response

Comparison of Bayesian penalized likelihood reconstruction versus OS-EM for characterization of small pulmonary nodules in oncologic PET/CT by Brandon A. Howard; Rustain Morgan; Matthew P. Thorpe; Timothy G. Turkington; Jorge Oldan; Olga G. James; Salvador Borges-Neto (623-628).
To determine whether the recently introduced Bayesian penalized likelihood PET reconstruction (Q.Clear) increases the visual conspicuity and SUVmax of small pulmonary nodules near the PET resolution limit, relative to ordered subset expectation maximization (OS-EM).In this institutional review board-approved and HIPAA-compliant study, 29 FDG PET/CT scans performed on a five-ring GE Discovery IQ were retrospectively selected for pulmonary nodules described in the radiologist’s report as “too small to characterize”, or small lung nodules in patients at high risk for lung cancer. Thirty-two pulmonary nodules were assessed, with mean CT diameter of 8 mm (range 2–18). PET images were reconstructed with OS-EM and Q.Clear with noise penalty strength β values of 150, 250, and 350. Lesion visual conspicuity was scored by three readers on a 3-point scale, and lesion SUVmax and background liver and blood pool SUVmean and SUVstdev were recorded. Comparison was made by linear mixed model with modified Bonferroni post hoc testing; significance cutoff was p < 0.05.Q.Clear improved lesion visual conspicuity compared to OS-EM at β = 150 (p < 0.01), but not 250 or 350. Lesion SUVmax was increased compared to OS-EM at β = 150 and 250 (p < 0.01), but not 350.In a cohort of small pulmonary nodules with size near an 8 mm PET full-width half maximum, Q.Clear significantly increased lesion visual conspicuity and SUVmax compared to our standard non- time-of-flight OS-EM reconstruction, but only with low noise penalization. Q.Clear with β = 150 may be advantageous when evaluation of small pulmonary nodules is of primary concern.
Keywords: FDG PET; PET/CT; Penalized likelihood reconstruction; Oncology

Comparison of CTAC and prone imaging for the detection of coronary artery disease using CZT SPECT by Shimpei Ito; Akihiro Endo; Taiji Okada; Taku Nakamura; Takashi Sugamori; Nobuyuki Takahashi; Hiroyuki Yoshitomi; Kazuaki Tanabe (629-635).
Cadmium-zinc-telluride (CZT) cameras have improved the evaluation of patients with chest pain. However, inferior/inferolateral attenuation artifacts similar to those seen with conventional Anger cameras persist. We added prone acquisitions and CT attenuation correction (CTAC) to the standard supine image acquisition and analyzed the resulting examinations.Seventy-two patients referred for invasive coronary angiography (CAG), and who also underwent rest/stress myocardial perfusion imaging (MPI) on a CZT camera in the supine and prone positions plus CTAC imaging, to examine known or suspected CAD between April 2013 and March 2014 were included. A sixteen-slice CT scan acquired on a SPECT/CT scanner between rest and stress imaging provided data for iterative reconstruction. Sensitivity, specificity, accuracy, and positive and negative likelihood ratios (LRs) were calculated to compare MPI with CAG on a per-patient basis. Per-patient sensitivity, specificity, and accuracy of supine images to predict coronary abnormalities on CAG were 35% [95% confidence interval (CI) 19–52], 86% (95% CI 80–92), and 74% (95% CI 66–82); those of prone imaging were 65% (95% CI 45–81), 82% (95% CI 76–87), and 78% (95% CI 68–85); and those of CTAC were 59% (95% CI 41–71), 93% (95% CI 87–97), and 85% (95% CI 76–91), respectively.Prone acquisition and CTAC images improve the ability to assess the inferior/inferolateral area.
Keywords: Single-photon emission computed tomography; Myocardial ischemia; Coronary artery disease

Design and evaluation of two multi-pinhole collimators for brain SPECT by Ling Chen; Benjamin M. W. Tsui; Greta S. P. Mok (636-648).
SPECT is a powerful tool for diagnosing or staging brain diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) but is limited by its inferior resolution and sensitivity. At the same time, pinhole SPECT provides superior resolution and detection efficiency trade-off as compared to the conventional parallel-hole collimator for imaging small field-of-view (FOV), which fits for the case of brain imaging. In this study, we propose to develop and evaluate two multi-pinhole (MPH) collimator designs to improve the imaging of cerebral blood flow and striatum.We set the target resolutions to be 12 and 8 mm, respectively, and the FOV at 200 mm which is large enough to cover the whole brain. The constraints for system optimization include maximum and minimum detector-to-center-of-FOV (CFOV) distances of 344 and 294 mm, respectively, and minimal radius-of-rotation (ROR) of 135 mm to accommodate patients’ shoulder. According to the targeted FOV, resolutions, and constraints, we determined the pinhole number, ROR, focal length, aperture acceptance angle, and aperture diameter which maximized the system sensitivity. We then assessed the imaging performance of the proposed MPH and standard low-energy high-resolution (LEHR) collimators using analytical simulations of a digital NCAT brain phantom with 99mTc-HMPAO/99mTc-TRODAT-1 distributions; Monte Carlo simulations of a hot-rod phantom; and a Defrise phantom using GATE v6.1. Projections were generated over 360° and reconstructed using the 3D MPH/LEHR OS-EM methods with up to 720 updates. The normalized mean square error (NMSE) was calculated over the cerebral and striatal regions extracted from the reconstructed images for 99mTc-HMPAO and 99mTc-TRODAT-1 simulations, respectively, and average normalized standard deviation (NSD) based on 20 noise realizations was assessed on selected uniform 3D regions as the noise index. Visual assessment and image profiles were applied to the results of Monte Carlo simulations.The optimized design parameters of the MPH collimators were 9 pinholes with 4.7 and 2.8 mm pinhole diameter, 73° acceptance angle, 127 mm focal length, 167 mm ROR for 12 mm and 8 mm target resolution, respectively. According to the optimization results, the detection efficiencies of the proposed collimators were 270 and 40% more as compared to LEHR. The Monte Carlo simulations showed that 7.9 and 6.4 mm rods can be discriminated for the MPH collimators with target resolutions of 12 and 8 mm, respectively. The eight 12 mm-thick discs of the Defrise phantom can also be resolved clearly in the axial plane as demonstrated by the image profiles generated with the MPH collimators.The two collimator designs provide superior image quality as compared to the conventional LEHR, and shows potential to improve current brain SPECT imaging based on a conventional SPECT scanner.
Keywords: Brain SPECT; Multi-pinhole; Alzheimer’s disease (AD); Parkinson’s disease (PD)