Nuclear Medicine

Development of a p38α-selective radioactive probe for qualitative diagnosis of cancer using SPECT Abstract Objective p38 mitogen-activated protein (MAP) kinase (p38α) has drawn attention as a new target molecule for the treatment and diagnosis of cancer, and its overexpression and activation have been reported in various types of cancer. In this study, a single photon emission computed tomography (SPECT) imaging probe of p38α was developed to noninvasively image p38α activity for effective qualitative diagnosis of cancer. Methods Pyrrolepyridine derivatives, m-YTM and p-YTM, were designed and synthesized based on the structure of the p38α-selective inhibitor. Radioactive iodine-labeled m-YTM, [125I]m-YTM, was synthesized because m-YTM greatly inhibited the phosphorylation of p38α upon examining the inhibitory effects of the compounds. After investigating the binding affinity of [125I]m-YTM to the recombinant p38α, a saturation binding experiment using activated p38α and inactive p38α was performed to determine the binding site. Uptake of [125I]m-YTM into various cancer cell lines was investigated, and the pharmacokinetics was evaluated using tumor-bearing mice. Results The inhibitory activity of m-YTM was approximately 13 times higher than that of SB203580, a p38α-selective inhibitor. The binding site of [125I]m-YTM was estimated to be the p38α activating site, similar to that of SB203580, because the [125I]m-YTM bound strongly to both activated p38α and inactive p38α. Various different cancer cells incorporated [125I]m-YTM; however, its accumulation was significantly reduced by treatment with SB203580. Pharmacokinetics study of [125I]m-YTM in B-16 tumor-bearing mice was examined which revealed high accumulation of radioactivity in tumor tissues. The ratios of radioactivity in the B-16 tumor to that in blood were 3.1 and 50 after 1 and 24 h, respectively. The ratio of radioactivity in the tumor to that in blood in the tumor-bearing mice generated using other cancer cell lines was also ≥ 1 at 1 h after the administration of the probe. Conclusions This study suggests that [123I]m-YTM has potential as a p38α imaging probe effective for various cancer types.

Development of radiolabeled bis(zinc(II)-dipicolylamine) complexes for cell death imaging Abstract Purpose Although it has been traditionally surmised that phosphatidylserine (PS) externalization is a hallmark of apoptosis, most other non-apoptotic modes of cell death, such as necrosis, are also associated with PS externalization. Bis(zinc-dipicolylamine) (ZnDPA) complexes have been reported to exhibit affinity for PS. The present study aimed to develop novel radiolabeled ZnDPA derivatives for cell death imaging in tumor after treatment with anticancer drugs. Methods [125I]IB-EG2-ZnDPA and [99mTc]Tc-MAG3-EG2-ZnDPA were designed and prepared. The stabilities of these radiotracers were determined in 0.1 M phosphate buffer (pH 7.4) or murine plasma at 37 °C, and their 1-octanol/water partition coefficients (logP) were measured. The uptake of radioactivity in cancer cells, which were preincubated in a normal medium or in a medium containing 5-FU, was measured after incubation with radiotracers. Accumulation of [99mTc]Tc-MAG3-EG2-ZnDPA in the tumor was evaluated in tumor-bearing mice treated with or without 5-FU, and then TUNEL staining was performed to detect dead cells in the tumor tissue sections. Results The radiochemical purities of [125I]IB-EG2-ZnDPA and [99mTc]Tc-MAG3-EG2-ZnDPA exceeded 95%. Although [125I]IB-EG2-ZnDPA gradually decomposing with time, more than 90% of [99mTc]Tc-MAG3-EG2-ZnDPA remained in its intact form in phosphate buffer through 6 h of incubation. Neither [125I]IB-EG2-ZnDPA nor [99mTc]Tc-MAG3-EG2-ZnDPA decomposed so much after 6-h incubation in murine plasma. [125I]IB-EG2-ZnDPA could not specifically recognize PS on the cell surface because of its high lipophilicity. Conversely, [99mTc]Tc-MAG3-EG2-ZnDPA accumulated in cancer cells after treatment with an anticancer drug both in vitro and in vivo, and its accumulation was correlated with the number of TUNEL-positive cells. However, the biodistribution of [99mTc]Tc-MAG3-EG2-ZnDPA was not suitable for imaging because of its low accumulation in tumor and high uptake in abdomen organs. Conclusion [99mTc]Tc-MAG3-EG2-ZnDPA could be useful for the early detection of treatment effects after chemotherapy. Since the signal-to-noise ratio is not enough for single photon emission computed tomography imaging, further modification is needed to improve its biodistribution and affinity for PS.

Accumulation of hypoxia imaging probe " 18 F-FMISO" in macrophages depends on macrophage polarization in addition to hypoxic state Abstract Objective Macrophages play an essential role in immune response, and are closely related to the progression of diseases such as cancer and atherosclerosis. Macrophages polarize to M1 or M2 type, which is related to the environmental hypoxic state. Previously, we found that 18F-FMISO uptake varied according to expression levels of biomolecules such as glutathione S-transferase P1 (GST-P1), which catalyzes the conjugation of glutathione to 18F-FMISO metabolites, and multidrug resistance-associated protein 1 (MRP1), which exports glutathione-18F-FMISO metabolite conjugates out of cells. However, the relationship between macrophage polarization and 18F-FMISO accumulation remains unclear. Methods Mouse peritoneal macrophages were polarized to either the M1 or M2 type, and were treated with 18F-FMISO. Then, their radioactivity after a 4 h incubation period under normoxic (21% O2) or hypoxic (1% O2) condition was measured. GST-P1 and MRP1 expression levels were measured by qRT-PCR. Results M2 macrophages exhibited a significantly higher uptake of 18F-FMISO than non-polarized (M0) macrophages, whereas M1 macrophages had a significantly lower uptake than M0 macrophages (M0: 1.05 ± 0.22, M1: 0.34 ± 0.02, M2: 4.17 ± 0.36 %dose/mg protein). The GST-P1 expression level in M1 macrophages was higher than that in M2 and M0 macrophages [GST-P1/β-actin normalized by M0: 9.0 ± 3.7 (M1), 1.2 ± 0.2 (M2)]. The MRP1 expression level in M1 macrophages was significantly higher than that in M2 and M0 macrophages [MRP1/β-actin normalized by M0 macrophages: 5.1 ± 2.1 (M1), 2.8 ± 1.0 (M2)]. Conclusions 18F-FMISO accumulation in macrophages may depend on the polarization state in addition to hypoxic condition.

Increased 18 F-FDG accumulation in the tonsils after chemotherapy for pediatric lymphoma: a common physiological phenomenon Abstract Objective Increased 18F-fluorodeoxyglucose (FDG) uptake in the tonsils after the completion of chemotherapy in patients with lymphoma may be misdiagnosed as tumor recurrence. This study aimed to investigate the changes in physiological FDG uptake in the tonsils during and after chemotherapy in pediatric patients with lymphoma. Methods A total of 47 FDG-PET/CT scans acquired from 13 pediatric patients with lymphoma (before chemotherapy [preC] = 9; during chemotherapy [durC] = 12; within 1 month after the end of chemotherapy [endC] = 11; and after achieving complete response [postC] = 15) were retrospectively included in this study. FDG uptake in the palatine tonsils was assessed using maximum standardized uptake value (SUVmax). The relative size of the palatine tonsils was calculated as the tonsil-pharyngeal ratio (TPR). Serial changes in the SUVmax and TPR were evaluated. Results The mean SUVmax was 3.7 ± 1.7, 2.6 ± 0.7, 2.3 ± 0.8, and 6.2 ± 1.6, at the preC, durC, endC, and postC scans, respectively (p < 0.0001); TPR was 59.0 ± 11.2%, 58.3 ± 9.4%, 54.4 ± 7.9%, and 62.2 ± 12.0% in these groups, respectively, with no significant inter-group differences. TPR and SUVmax showed no correlation. Conclusions Increased physiological FDG uptake in the tonsils is commonly observed after the completion of chemotherapy, even in the absence of reactive hypertrophy.

Effect of respiratory motion on cardiac defect contrast in myocardial perfusion SPECT: a physical phantom study Abstract Objective Correction for respiratory motion in myocardial perfusion imaging requires sorting of emission data into respiratory windows where the intra-window motion is assumed to be negligible. However, it is unclear how much intra-window motion is acceptable. The aim of this study was to determine an optimal value of intra-window residual motion. Methods A custom-designed cardiac phantom was created and imaged with a standard dual-detector SPECT/CT system using Tc-99m as the radionuclide. Projection images were generated from the list-mode data simulating respiratory motion blur of several magnitudes from 0 (stationary phantom) to 20 mm. Cardiac defect contrasts in six anatomically different locations, as well as myocardial perfusion of apex, anterior, inferior, septal and lateral walls, were measured at each motion magnitude. Stationary phantom data were compared to motion-blurred data. Two physicians viewed the images and evaluated differences in cardiac defect visibility and myocardial perfusion. Results Significant associations were observed between myocardial perfusion in the anterior and inferior walls and respiratory motion. Defect contrasts were found to decline as a function of motion, but the magnitude of the decline depended on the location and shape of the defect. Defects located near the cardiac apex lost contrast more rapidly than those located on the anterior, inferior, septal and lateral wall. The contrast decreased by less than 5% at every location when the motion magnitude was 2 mm or less. According to a visual evaluation, there were differences in myocardial perfusion if the magnitude of the motion was greater than 1 mm, and there were differences in the visibility of the cardiac defect if the magnitude of the motion was greater than 9 mm. Conclusions Intra-window respiratory motion should be limited to 2 mm to effectively correct for respiratory motion blur in myocardial perfusion SPECT.

Evaluation of whole-body tumor burden with 68 Ga-PSMA PET/CT in the biochemical recurrence of prostate cancer Abstract Background 68 Ga-PSMA-PET has an increasing importance in the evaluation of prostate cancer patients due to its high sensitivity and specificity in identifying neoplastic lesions in the clinical setting of elevated prostate-specific antigen (PSA). The objective of this study was to calculate the whole-body tumor burden using volumetric quantification of lesions detected in 68Ga-PSMA-PET of prostate cancer patients with biochemical recurrence and correlate these findings with clinical and image parameters. Methods Each patient had their 68Ga-PSMA-PET analyzed for the presence of neoplastic lesions. Their PSA levels and clinical information were recorded. In positive cases, the tumor burden (TL-PSMA) was calculated with a semi-automatic software and manually, and the results are analyzed and tested. Results We analyzed 100 prostate cancer patients, mean age of 69.9 ± 9.7 years and a median PSA of 1.73 ng/dL. 68Ga-PSMA-PET identified neoplastic lesions in 72% of them. The median TL-PSMA was 55.95 ml (1.1–28,080 ml). TL-PSMA and PSA were strongly correlated (rho = 0.71, p < 0.0001, 95% CI 0.60–0.80). TL-PSMA and PSA levels groups had a significant correlation and TL-PSMA and Gleason score were independent variables associated with PSA levels (p < 0.05). Conclusion TL-PSMA strongly and independently correlates with PSA levels in prostate cancer patients and could be used as a biomarker to separate them into groups with high or low tumor burden, instead of considering only the number of lesions.

Clinicopathological predictors of positive 68 Ga-PSMA-11 PET/CT in PSA-only recurrence of localized prostate cancer following definitive therapy Abstract Objective To demonstrate the effect of clinicopathological factors on 68Ga-PSMA-11 PET/CT positivity at the time of biochemical recurrence (BCR) of localized prostate cancer (PCa) following definitive therapy. Methods We retrospectively reviewed our institutional database for PCa patients who had BCR and subsequently underwent 68Ga-PSMA-11 PET/CT between April 2014 and February 2018. A total of 51 patients who were metastasis-free before PSMA imaging and previously treated with definitive therapy (radical prostatectomy or external beam radiotherapy) for localized disease (pT1c—T3b pN0-1 cM0) were included. Results 37 out of 51 patients (72.5%) had positive 68Ga-PSMA-11 PET/CT scans. Age at diagnosis, Gleason score (GS), D'Amico risk status of PCa, initial PSA level before treatment and PSA doubling time were not associated with PSMA positivity. Pre-scan PSA levels of > 0.2 ng/ml and PSA velocity of ≥ 1 ng/ml/year were significantly associated with increased PSMA positivity, whereas history of androgen deprivation therapy showed a trend towards significance. The optimal cutoffs for distinguishing between positive and negative scans were ≥ 0.71 ng/ml for pre-scan PSA and ≥ 1.22 ng/ml/yr for PSA velocity. In multivariable analysis, log pre-scan PSA and pre-scan PSA level > 0.2 ng/ml remained significant predictors for PSMA positivity, whereas the association of PSA velocity and of ADT was lost. Conclusions In BCR of localized PCa following definitive therapy, pre-scan PSA was strongly associated with positive 68Ga-PSMA-11 scan, even at PSA levels ranging from 0.2 to 1.0 ng/ml. Therefore, clinical and pathological predictors of positive 68Ga-PSMA-11 PET/CT in PSA-only recurrence of localized prostate cancer need to be further elucidated.

18 F-NaF-PET/CT for the detection of bone metastasis in prostate cancer: a meta-analysis of diagnostic accuracy studies Abstract Purpose This meta-analysis aims to establish the diagnostic performance of 18F-NaF-PET/CT for the detection of bone metastases in prostate cancer patients. The performance of 18F-NaF-PET/CT was compared with other imaging techniques in the same cohort of patients. Methods A systematic search was performed in PubMed/Medline and EMBASE (last Updated, September 28, 2018). Studies with histopathology confirmation and/or clinical/imaging follow-up as reference standard were eligible for inclusion. Results A total of 14 studies were included. Twelve studies including 507 patients provided per-patient basis information. The pooled sensitivity, specificity, diagnostic odds ratio (DOR) and the area under the summary receiver operating characteristics curve (AUC) of 18F-NaF-PET/CT for the detection of bone metastases were 0.98 (95% CI 0.95–0.99), 0.90 (95% CI 0.86–0.93), 123.2 and 0.97, respectively. Seven studies provided the lesion-based accuracy information of 1812 lesions identified on 18F-NaF-PET/CT with the pooled sensitivity, specificity, DOR and AUC of 0.97 (95% CI 0.95–0.98), 0.84 (95% CI 0.81–0.87), 206.8 and 0.97, respectively. The overall diagnostic performance of 18F-NaF-PET/CT is superior to 99mTc-bone scintigraphy (AUC 0.842; P < 0.001; four studies) and 99mTc-SPECT (AUC 0.896; P < 0.001, four studies). Compared to 18F NaF-PET/CT, whole-body MRI with diffusion-weighted imaging (DWI) was shown to have lower sensitivity (0.83, 95% CI 0.68–0.93), with no significant difference in the overall performance (AUC 0.947; P = 0.18, four studies). Conclusion 18F-NaF-PET/CT has excellent diagnostic performance in the detection of bone metastases in staging and restaging of high-risk prostate cancer patients. The performance of 18F-NaF-PET/CT is superior to 99mTc bone scintigraphy and SPECT, and comparable to DWI–MRI.

A novel biomarker, active whole skeletal total lesion glycolysis (WS-TLG), as a quantitative method to measure bone metastatic activity in breast cancer patients Abstract Objective There is no good response evaluation method for skeletal metastasis. We aimed to develop a novel quantitative method to evaluate the response of skeletal metastasis, especially lytic lesions, for treatment. Methods A method to measure active bone metastatic burden quantitatively using F-18 fluorodeoxyglucose positron emission tomography with computed tomography (FDG–PET/CT) in breast cancer patients, whole skeletal total lesion glycolysis (WS-TLG), a summation of each skeletal lesion's TLG, was developed. To identify active bone lesions, a tentative cutoff value was decided using FDG–PET/CT in 85 breast cancer patients without skeletal metastasis and 35 with skeletal metastasis by changing the cutoff value. Then, the WS-TLG method was evaluated by comparing to PET Response Criteria in Solid Tumor (PERCIST) or European Organization for Research and Treatment of Cancer (EORTC) criteria for only bone in 15 breast cancer patients with skeletal metastasis who were treated. Results A cutoff value of the standardized uptake value (SUV) = 4.0 gave 91% (77/85) specificity and 97% (34/35) sensitivity. We decided on SUV = 4.0 as a tentative cutoff value. Skeletal metastases of lytic and mixed types showed higher WS-TLG values than those of blastic or intertrabecular types, although statistical significance was not tested. All 15 patients showed agreement with PERCIST or EORTC in the therapeutic bone response. Conclusion This quantitative WS-TLG method appears to be a good biomarker to evaluate skeletal metastasis in breast cancer patients, especially lytic or mixed types. Further clinical studies are warranted to assess the clinical values of this new WS-TLG method.

Measurement of cerebral vascular reserves with I-123 IMP SPECT without an arterial input function using the microsphere model and radiopharmaceutical dose calibration Abstract Objectives Cerebral vascular reserve (CVR) is an important indicator for the management of and therapy for cerebral arterial occlusive disease (CAOD). Vasodilatory function is measured using the standard IMP-ARG method. The IMP autoradiography (IMP-ARG) method employed here uses a standardized input function, which was derived from 12 patients between 31 and 71 years of age. Because the population of elderly patients continues to increase in Japan, additional therapies are required to assess CVR in elderly patients with chronic cardiopulmonary disease or a history of smoking, in particular. Despite its popularity, alternatives to the IMP-ARG method are necessary. Here, we proposed the microsphere (MS) method without an input function. Method Using this method and the IMP-ARG method, we measured the CVRs of 18 CAOD patients. Results The CVRs derived with these two methods were significantly and linearly correlated (r = 0.89, p < 0.01). CVRs categorized by severity were also found to correspond between the two methods (κ = 0.87). Conclusions Thus, the method proposed here may serve as a supplemental to and be compatible with the IMP-ARG method for the assessment of CVR. Furthermore, the two methods, when used in conjunction, may result in less error than either would alone.