Nuclear Medicine

Preliminary results of biodistribution and dosimetric analysis of [ 68 Ga]Ga-DOTA ZOL : a new zoledronate-based bisphosphonate for PET/CT diagnosis of bone diseases Abstract Objective Pre-clinical studies with gallium-68 zoledronate ([68Ga]Ga-DOTAZOL) have proposed it to be a potent bisphosphonate for PET/CT diagnosis of bone diseases and diagnostic counterpart to [177Lu]Lu-DOTAZOL and [225Ac]Ac-DOTAZOL. This study aims to be the first human biodistribution and dosimetric analysis of [68Ga]Ga-DOTAZOL. Methods Five metastatic skeletal disease patients (mean age: 72 years, M: F; 4:1) were injected with 150–190 MBq (4.05–5.14 mCi) of [68Ga]Ga-DOTAZOL i.v. Biodistribution of [68Ga]Ga-DOTAZOL was studied with PET/CT initial dynamic imaging for 30 min; list mode over abdomen (reconstructed as six images of 300 s) followed by static (skull to mid-thigh) imaging at 45 min and 2.5 h with Siemens Biograph 2 PET/CT camera. Also, blood samples (8 time points) and urine samples (2 time points) were collected over a period of 2.5 h. Total activity (MBq) in source organs was determined using interview fusion software (MEDISO Medical Imaging Systems, Budapest, Hungary). A blood-based method for bone marrow self-dose determination and a trapezoidal method for urinary bladder contents residence time calculation were used. OLINDA/EXM version 2.0 software (Hermes Medical Solutions, Stockholm, Sweden) was used to generate residence times for source organs, organ absorbed doses and effective doses. Results High uptake in skeleton as target organ, kidneys and urinary bladder as organs of excretion and faint uptake in liver, spleen and salivary glands were seen. Qualitative and quantitative analysis supported fast blood clearance, high bone to soft tissue and lesion to normal bone uptake with [68Ga]Ga-DOTAZOL. Urinary bladder with the highest absorbed dose of 0.368 mSv/MBq presented the critical organ, followed by osteogenic cells, kidneys and red marrow receiving doses of 0.040, 0.031 and 0.027 mSv/MBq, respectively. The mean effective dose was found to be 0.0174 mSv/MBq which results in an effective dose of 2.61 mSv from 150 MBq. Conclusions Biodistribution of [68Ga]Ga-DOTAZOL was comparable to [18F]NaF, [99mTc]Tc-MDP and [68Ga]Ga-PSMA-617. With proper hydration and diuresis to reduce urinary bladder and kidney absorbed doses, it has clear advantages over [18F]NaF owing to its onsite, low-cost production and theranostic potential of personalized dosimetry for treatment with [177Lu]Lu-DOTAZOL and [225Ac]Ac-DOTAZOL.

Preliminary clinical assessment of dynamic 18 F-fluorodeoxyglucose positron emission tomography/computed tomography for evaluating lymph node metastasis in patients with lung cancer: a prospective study Abstract Objective We assessed the diagnostic capacity of dynamic fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and dual-time-point (DTP) PET/CT to explore the optimal scan timing for nodal staging in lung cancer. Methods Thirty-four patients with lung cancer underwent dynamic and consecutive DTP PET/CT scans. Two readers visually evaluated FDG uptake within each lymph node (LN) and pulmonary artery (metastatic LN: n = 10; nonmetastatic LN: n = 121). For each dynamic and DTP scan, we compared the maximum standardized uptake value (SUVmax) and the retention index of the SUVmax (RI-SUVmax) between metastatic and nonmetastatic LNs. We compared the diagnostic capacity of the dynamic and DTP scans using receiver operating characteristic (ROC) analyses. Results In the visual analyses of LN metastases, a sensitivity of 20.0–60.0% and specificity of 97.5–100.0% were identified for the first to third dynamic scans. The sensitivity of the 1-h early and 2-h delayed scans was 80.0% and 90.0%, respectively, whereas the specificity was 66.9% and 47.9%, respectively. The visual analysis of the dynamic second phase had the highest accuracy. Semiquantitative analyses revealed that the SUVmax was significantly higher for metastatic LNs than for nonmetastatic LNs in the dynamic second and third phases and the 1-h early and 2-h delayed phases (p < 0.05 for all). The RI-SUVmax was higher in metastatic LNs than in nonmetastatic LNs for the dynamic scan (p = 0.004) and the DTP scan (p = 0.002). The ROC analyses showed that SUV2 and SUV3 had higher performances with high specificity, high negative predictive value, and high accuracy than the other parameters. The area under the ROC curve of the RI-SUV-dual-time-point had the highest value (0.794) without any significant differences between the area under the ROC curves for all parameters (p > 0.05 for all). Conclusions Based on the visual and semiquantitative analyses, 18F-FDG dynamic PET/CT exhibited excellent performance with extremely high specificity in the dynamic second phase.

Distribution of LAT1-targeting PET tracer was independent of the tumor blood flow in rat xenograft models of C6 glioma and MIA PaCa-2 Abstract Objective L-type amino acid transporter 1 (LAT1) is strongly expressed on the cell membrane in various types of human cancer cells, while being minimally expressed in normal or inflammatory tissues. Therefore, LAT1-targeting PET tracers have been developed for cancer-specific imaging. The purpose of this study was to study the distribution of two LAT1-targeting PET tracers, L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) and L-3-18F-alpha-methyl tyrosine (18F-FAMT), in relation to the tumor blood flow, using rat xenograft models. Methods Rat tumor xenograft models of C6 glioma (n = 4; tumors = 8) and MIA PaCa-2 (pancreatic cancer) (n = 4; tumors = 6) were used. The expressions of LAT1 and CD98hc were evaluated by both immunofluorescence staining and western blot analysis. Dynamic PET was performed after injection of 18F-FAMT or 18F-FBPA (scan duration = 70 min) following 15O-water PET (scan duration = 10 min). The PET data were subjected to kinetic analyses, and the K1, k2, and total distribution volume (Vt) were calculated using the one-tissue compartment model. The accumulation of the LAT1 tracers was expressed in terms of their Vt. Tumor blood flow (TBF) was represented by the K1 value in 15O-water PET. Results LAT1/CD98hc expression was confirmed in both xenografts by immunofluorescence staining. Western blot analysis showed higher functional expression of LAT1 in the C6 glioma cells as compared to the MIA PaCa-2 cells (C6 glioma/MIA PaCa-2 relative expression ratio = 1.70). The Vt values of both 18F-FBPA and 18F-FAMT were significantly higher in the C6 glioma xenografts than in the MIA PaCa-2 xenografts (C6 glioma: 2.27 ± 0.35 and 2.03 ± 0.23, respectively; MIA PaCa-2: 1.28 ± 0.26 and 1.35 ± 0.15, respectively). Meanwhile, there was no significant correlation of the Vt value of either 18F-FBPA or 18F-FAMT with the TBF, in either the C6 glioma or the MIA PaCa-2 xenografts. Conclusions This study revealed that total distribution volumes of the LAT1-targeting PET tracers 18F-FBPA and 18F-FAMT were independent of the tumor blood flow and might reflect the functional expression levels of LAT1 in the C6 glioma and MIA PaCa-2 xenograft models.

Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site Abstract Objective Amyloid-β plaques and neurofibrillary tangles composed of tau protein are the neuropathological hallmarks of Alzheimer's disease. In recent years, marked progress has been made in Alzheimer's disease research using tau ligands for positron emission tomography (PET). However, the issue of off-target binding, that is, the binding of ligands to regions without tau pathology, remains unresolved. Tissues with melanin-containing cells (MCCs) have been suggested as binding targets for tau ligands. In the present study, we characterized the MCC-binding properties of representative tau PET ligands. Methods Autoradiographic studies of [18F]AV-1451 and [18F]THK5351 were conducted using postmortem human midbrain sections. Saturation-binding assays of [18F]AV-1451 and [18F]THK5351 were performed with B16F10 melanoma cells. The blocking effects of 25 compounds against [18F]THK5351 binding to B16F10 cells were used to investigate the relationship between chemical structure and MCC binding. Results Autoradiography demonstrated specific binding of the radioligands in the substantia nigra. [18F]AV-1451 and [18F]THK5351 exhibited saturable binding to melanoma cells ([18F]AV-1451: Kd = 669 ± 196 nM, Bmax = 622 ± 269 pmol/mg protein; [18F]THK5351: Kd = 441 ± 126 nM, Bmax = 559 ± 75.5 pmol/mg protein). In blocking studies with melanoma cells, compounds bearing multiple aromatic rings and an aminopyridine group, including tau ligands such as AV-1451, PBB3, and a lead compound of MK-6240, exhibited the inhibition of [18F]THK5351 binding comparable to self-blocking by THK5351 (> 70% at 10 µM). Conclusions These studies suggest that the binding properties of [18F]AV-1451 and [18F]THK5351 are sufficient to expect highlighting of tissues with a high density of MCCs. The findings of the present study should aid the development of neuroimaging ligands that do not bind to MCC.

Potential utility of bone scan in cranial bone flap osteomyelitis Abstract Objective Currently, the diagnosis of bone flap osteomyelitis (BFO) remains a challenge for medical imaging. The present study aimed to identify predictive scintigraphic patterns of BFO. Methods This retrospective study reviewed planar bone scan of patients with suspected BFO between 2010, and 2016. A total of 15 patients were included. Final diagnosis of BFO was obtained by histological and bacteriological documentation. Eight scintigraphic signs potentially helpful were reviewed and correlated with the final diagnosis individually or in combination through Fischer exact test. Results Eight patients out of 15 (53.3%) were diagnosed with BFO. Radionuclide uptake inside the bone flap during blood-pool phase was predictive for BFO (p = 0.007) with 75.0% sensitivity 100% specificity, and 86.7% accuracy. In combination, radionuclide uptake inside the bone flap or a spreading wavefront between blood-pool and delayed phases was associated with BFO (p = 0.007). It did not improve diagnostic performance. Conclusion Using well-defined and reproducible scintigraphic signs, bone scan is helpful for the diagnosis of BFO.

Novel 3D heart left ventricle muscle segmentation method for PET-gated protocol and its verification Abstract Objective The aim of this study was to propose and verify a universal method of left ventricular myocardium segmentation, able to operate on heart gated PET data with different sizes, shapes and uptake distributions. The proposed method can be classified as active model method and is based on the BEAS (B-spline Explicit Active Surface) algorithm published by Barbosa et al. The method was implemented within the Pmod PCARD software package. Method verification by comparison with reference software and phantom data is also presented in the paper. Methods The proposed method extends the BEAS model by defining mechanical features of the model: tensile strength and bending resistance. Formulas describing model internal energy increase during its stretching and bending are proposed. The segmentation model was applied to the data of 60 patients, who had undergone cardiac gated PET scanning. QGS by Cedars-Sinai and ECTb by Emory University Medical Centre served as reference software for comparing ventricular volumes. The method was also verified using data of left ventricular phantoms of known volume. Results The results of the proposed method are well correlated with the results of QGS (slope: 0.841, intercept: 0.944 ml, R2: 0.867) and ECTb (slope: 0.830, intercept: 2.109 ml, R2: 0.845). The volumes calculated by the proposed method were very close to the true cavity volumes of two different phantoms. Conclusions The analysis of gated PET data by the proposed method results in volume measurements comparable to established methods. Phantom experiments demonstrate that the volume values correspond to the physical ones.

The use of 3′-deoxy-3′- 18 F-fluorothymidine (FLT) PET in the assessment of long-term survival in breast cancer patients treated with neoadjuvant chemotherapy Abstract Objective To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. Methods This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUVmean was derived using an isocontour ROI drawn approximately half way between the SUVmax and background on three planes for each scan. The change in mean standardized uptake value (SUVmean) for the primary tumor between these two scans was then calculated, and patients were stratified into "responder" and "non-responder" groups based on a cut-off of 20% arithmetic decrease in SUVmean between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. Results 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them "responders". The remaining nine patients were "non-responders" to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. Conclusion Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

123 I-FP-CIT striatal binding ratios do not decrease significantly with age in older adults Abstract Objective I-123-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) imaging is an established biomarker used in the diagnosis of Lewy body disease. Images are often reported with the aid of striatal binding ratios (SBRs), comparing uptake to a normal database via Z scores. It is well known that SBRs are age dependent. However, previous studies cover wide age ranges between 20 and 80 years, rather than focusing on older adults. Typically a linear relationship is reported, but some authors have suggested that SBRs do not decline as rapidly in old age. Commercial software packages usually adjust the SBR Z score to attempt to compensate for age-related decline, but the model used varies. Ensuring age correction is appropriate for older adults is important, given that the majority of patients referred for FP-CIT scans are aged over 60 years. We examined the relationship of SBR with age in older adults and the effect of age correction using research scans from 123 adults over 60 years of age. Methods Twenty-nine healthy older adults and twenty-three with MCI due to Alzheimer's disease were included as controls, i.e. individuals with no evidence of Lewy body disease. Their ages ranged from 60 to 92 years (mean 76; SD 7.9). SBRs and Z scores were calculated using BRASS (Hermes Medical) and DaTQUANT (GE Healthcare). SBRs were plotted against age and linear mixed effect models applied. We tested the effect of removing age correction in BRASS using an independent dataset of 71 older adults with dementia or mild cognitive impairment. Results The slopes of the linear fits between SBR and age per year were − 0.007 (p = 0.30) with BRASS and − 0.004 (p = 0.35) with DaTQUANT. The slopes are smaller than reported in the literature and show no statistically significant difference from zero. Switching age correction off in BRASS in the test subjects reduced Z scores by approximately 1 standard deviation at 80 years of age. Conclusion We found no statistically significant age-related decline in SBR in adults over 60 years of age without Lewy body disease. Commercial software packages that apply a fixed rate of age correction may be overcorrecting for age in older adults, which could contribute to misdiagnosis.

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.

Improved identification of patients with oligometastatic clear cell renal cell carcinoma with PSMA-targeted 18 F-DCFPyL PET/CT Abstract Objective Complete surgical resection of metastatic sites has been shown to prolong survival in select patients with oligometastatic RCC. This treatment strategy is dependent upon the accurate characterization of a patient's extent of disease. The objective of this study was to explore the utility of PSMA-targeted 18F-DCFPyL PET/CT in patients with presumed oligometastatic clear cell RCC. Methods This is a subset analysis of a prospective study in which patients with RCC were imaged with 18F-DCFPyL PET/CT (ClinicalTrials.gov identifier NCT02687139). In the present analysis, patients with oligometastatic clear cell RCC, defined as ≤ 3 metastatic lesions on conventional imaging, were evaluated. 18F-DCFPyL PET/CT scans were reviewed for sites of disease and compared to conventional imaging. Results The final cohort included 14 patients with oligometastatic clear cell RCC. Conventional imaging revealed 21 metastatic lesions and 3 primary tumors. 18F-DCFPyL PET/CT detected 29 sites of metastatic disease and 3 primary tumors. Of the 21 metastatic lesions detected on conventional imaging, 17 (81.0%) had radiotracer uptake. Additionally, all 3 primary tumors had radiotracer uptake. In 4 (28.6%) patients a total of 12 more lesions were identified on 18F-DCFPyL PET/CT than conventional imaging. Notably, 3 (21.4%) patients were no longer considered oligometastatic. The detection rates of conventional imaging and 18F-DCFPyL PET/CT for identifying sites of disease were 66.7% and 88.9%, respectively. Conclusions PSMA-targeted PET/CT appears to aid in the identification of patients with oligometastatic clear cell RCC. If borne out in future studies, this suggests that PSMA-targeted imaging has the potential to help select candidates for metastasis-directed therapy.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com