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Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of 68 Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis ( n = 2), rheumatoid arthritis-associated ILD ( n = 1), and nonspecific interstitial pneumonia ( n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUV max and SUV mean showed a positive correlation with the immunohistochemical FAP expression score (SUV max : r = 0.57, P = 0.001; SUV mean : r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: Prostate-specific membrane antigen (PSMA) radioguided salvage pelvic lymph node dissection (S-PLND) has emerged as a feasible treatment option for prostate cancer recurrence following initial surgery. This study aims to evaluate the feasibility and short-term outcomes of PSMA radioguided S-PLND., Methods: From a prospective trial of 99m Tc-PSMA-I&S followed by PSMA radioguided robotic surgery, we evaluated patients treated for node-only recurrence following radical therapy. The primary outcome was serum prostate-specific antigen (PSA) response 3 mo after surgery., Key Findings and Limitations: Among 14 patients (enrolled from June 2021 to June 2023), the median age was 65 yr. One patient had undergone primary whole gland ultrasound ablation, while the rest received prior prostatectomy. The median (interquartile range) time from primary treatment to PSMA positron emission tomography (PET) was 4.1 (2.9-8.3) yr, and 21 total pelvic targets were noted on PSMA PET: one in eight patients (67%), two in five patients (29%), and three in one patient (7%). Targets were successfully detected intraoperatively and removed in 13/14 (93%) patients. Cancer was noted on histopathology in 90% (19/21) of PSMA PET targets, 94% (17/18) of single-photon emission computed tomography targets, and 82% (14/17) of gamma probe targets. There were no adverse effects due to the radiotracer, and there were no complications after surgery. PSA at 3 mo was <0.2 ng/ml in two (14%) patients, and a ≥50% decline was noted in five (36%) patients. After a mean follow-up of 8.3 mo, the median time to next treatment was 11.7 mo, which was noted in nine patients., Conclusions and Clinical Implications: PSMA radioguided S-PLND is feasible and safe. However, the clinical role and the honing of technique and patient selection will be required in prospective studies., Patient Summary: In 14 patients who had prostate cancer recurrence after their initial treatment, performing surgery using radioactive tags to location is possible. However, futures studies are still needed to improve the technique., (© 2024 The Author(s).)

Novel theranostic approaches using radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have emerged for treating metastatic castration-resistant prostate cancer. The physical properties and commercial availability of 177 Lu make it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this literature review, we aimed at comparing the dosimetry of the most used [ 177 Lu]Lu-PSMA RPT compounds. Methods: This was a systematic review and metaanalysis of [ 177 Lu]Lu-PSMA RPT (617, I&T, and J591) dosimetry in patients with prostate cancer. Absorbed doses in Gy/GBq for each organ at risk (kidney, parotid and submandibular glands, bone marrow, liver, and lacrimal glands) and for tumor lesions (bone and nonbone lesions) were extracted from included articles. These were used to estimate the pooled average absorbed dose of each agent in Gy/GBq and in Gy/cycle, normalized to the injected activity (per cycle) used in the VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT trials (5.8 GBq). Results: Twenty-nine published articles comprising 535 patients were included in the metaanalysis. The pooled doses (weighted average across studies) of [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T were 4.04 Gy/GBq (17 studies, 297 patients) and 4.70 Gy/GBq (10 studies, 153 patients) for the kidney ( P = 0.10), 5.85 Gy/GBq (14 studies, 216 patients) and 2.62 Gy/GBq (5 studies, 86 patients) for the parotids ( P < 0.01), 5.15 Gy/GBq (5 studies, 81 patients) and 4.35 Gy/GBq (1 study, 18 patients) for the submandibular glands ( P = 0.56), 11.03 Gy/GBq (6 studies, 121 patients) and 19.23 Gy/GBq (3 studies, 53 patients) for the lacrimal glands ( P = 0.20), 0.24 Gy/GBq (12 studies, 183 patients) and 0.19 Gy/GBq (4 studies, 68 patients) for the bone marrow ( P = 0.31), and 1.11 Gy/GBq (9 studies, 154 patients) and 0.56 Gy/GBq (4 studies, 56 patients) for the liver ( P = 0.05), respectively. Average tumor doses tended to be higher for [ 177 Lu]Lu-PSMA-617 than for [ 177 Lu]Lu-PSMA-I&T in soft tissue tumor lesions (4.19 vs. 2.94 Gy/GBq; P = 0.26). Dosimetry data of [ 177 Lu]Lu-J591 were limited to one published study of 35 patients with reported absorbed doses of 1.41, 0.32, and 2.10 Gy/GBq to the kidney, bone marrow, and liver, respectively. Conclusion: In this metaanalysis, there was no significant difference in absorbed dose between [ 177 Lu]Lu-PSMA-I&T and [ 177 Lu]Lu-PSMA-617. There was a possible trend toward a higher kidney dose with [ 177 Lu]Lu-PSMA-I&T and a higher tumor lesion dose with [ 177 Lu]Lu-PSMA-617. It remains unknown whether this finding has any clinical impact. The dosimetry methodologies were strikingly heterogeneous among studies, emphasizing the need for standardization., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using 177 Lu or 225 Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or "tandem" approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus β-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. Methods: First, to determine comparable injected activities from 177 Lu- and 225 Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of 177 Lu- or 225 Ac-PSMA-617 alone or in combination (35 MBq of 177 Lu, 40 kBq of 225 Ac, or 17 MBq of 177 Lu + 20 kBq 225 Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. Results: The ex vivo biodistribution studies revealed that 35 MBq of 177 Lu and 40 kBq of 225 Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with 177 Lu was not significantly different from that of untreated mice. However, 225 Ac-PSMA-617 both as a single agent and in combination with 177 Lu (17 MBq of 177 Lu + 20 kBq of 225 Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for 177 Lu, 15.3 wk for 225 Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between 225 Ac alone and administration of half the 225 Ac activity in tandem with 177 Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for 177 Lu, 14.6 wk for 225 Ac alone, and 13.2 wk for tandem therapy). Conclusion: Treatment of a disseminated model of prostate cancer with simultaneous 225 Ac- and 177 Lu-PSMA-617 results in significantly decreased tumor growth compared with 177 Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of 177 Lu and 225 Ac. Although the greatest benefits were observed with the single agent 225 Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of 225 Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of 225 Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

In radiopharmaceutical therapy, intratumoral uptake of radioactivity usually leads to heterogeneous absorbed dose distribution. The likelihood of treatment success can be estimated with the tumor control probability (TCP), which requires accurate dosimetry, estimating the absorbed dose rate per unit activity to individual tumor cells. Methods: Xenograft cryosections of the prostate cancer cell line LNCaP treated with [ 177 Lu]Lu-PSMA-617 were evaluated with digital autoradiography and stained with hematoxylin and eosin. The digital autoradiography images were used to define the source in a Monte Carlo simulation of the absorbed dose, and the stained sections were used to detect the position of cell nuclei to relate the intratumoral absorbed dose heterogeneity to the cell density. Simulations were performed for 225 Ac, 177 Lu, and 90 Y. TCP was calculated to estimate the mean necessary injected activity for a high TCP. A hypothetical case of activity mainly taken up on the tumor borders was generated and used to simulate the absorbed dose. Results: The absorbed dose per decay to tumor cells was calculated from the staining and simulation results to avoid underestimating the tumor response from low absorbed doses in tumor regions with low cell density. The mean of necessary injected activity to reach a 90% TCP for 225 Ac, 177 Lu, and 90 Y was found to be 18.3 kBq (range, 18-22 kBq), 24.3 MBq (range, 20-29 MBq), and 5.6 MBq (range, 5-6 MBq), respectively. Conclusion: To account for the heterogeneous absorbed dose generated from nonuniform intratumoral activity uptake, dosimetry models can estimate the mean necessary activity to reach a sufficient TCP for treatment response. This approach is necessary to accurately evaluate the efficacy of suggested radiopharmaceuticals for therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: To assess the efficacy of 177 Lu-PNT2002, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in combination with stereotactic body radiotherapy (SBRT) to all sites of metastasis, vs SBRT alone, in men with oligorecurrent metastatic hormone-sensitive prostate cancer (mHSPC)., Patients and Methods: The 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR) trial is an open-label, randomized, stratified, two-arm, single-centre, Phase 2 trial to compare the efficacy and safety of neoadjuvant 177 Lu-PNT2002 plus SBRT vs SBRT alone in men with oligorecurrent mHSPC. Key eligibility criteria include one to five lesions identified on a PSMA positron emission tomography (PET)/computed tomography (CT) scan centrally reviewed by a board-certified nuclear medicine physician. Key exclusion criteria include castrate-resistant disease, de novo oligometastatic disease and receipt of androgen deprivation therapy (ADT) within 6 months of trial enrolment. The trial aims to enrol 100 patients who will be centrally randomized to one of the two treatment arms, in a 1:1 ratio. Patients in the control arm receive SBRT to all sites of disease. Patients in the experimental arm receive two cycles of neoadjuvant 177 Lu-PNT2002 (6.8 GBq) 6-8 weeks apart, followed by an interval PSMA PET/CT in 4-6 weeks and dose-adapted SBRT to all sites of disease 1-2 weeks later. The primary endpoint is progression-free survival. Secondary endpoints are radiographic and prostate-specific antigen-based progression, acute and late physician-scored toxicity, patient-reported quality of life, ADT-free survival, time to progression, overall survival, locoregional control, and duration of response. Enrolment in the study commenced in September 2022., Results and Conclusions: The addition of 177 Lu-PNT2002 to metastasis-directed therapy alone may potentially further forestall disease progression. The results of this Phase 2 trial will determine, for the first time in a randomized fashion, the added benefit of 177 Lu-PNT2002 to SBRT in patients with oligorecurrent mHSPC., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: To investigate model-fitted fractional myocardial blood volume (fMBV) derived from ferumoxytol-enhanced MRI as a measure of myocardial tissue hypoperfusion at rest., Methods: We artificially induced moderate to severe focal coronary stenosis in the left anterior descending artery of 19 swine by percutaneous delivery of a 3D-printed coronary implant. Using the MOLLI pulse sequence, we acquired T 1 maps at 3 T after multiple incremental ferumoxytol doses (0.0-4.0 mg/kg). We computed pixel-wise fMBV using a multi-compartmental modeling approach in 19 ischemic swine and 4 healthy swine., Results: Ischemic myocardial segments showed a mean MRI-fMBV of 11.72 ± 3.00%, compared with 8.23 ± 2.12% in remote segments and 8.38 ± 2.23% in normal segments. Ischemic segments showed a restricted transvascular water-exchange rate (k i  = 15.32 ± 8.69 s -1 ) relative to remote segments (k i  = 17.78 [11.60, 26.36] s -1 ). A mixed-effects model found significant difference in fMBV (p = 0.002) and water-exchange rate (p < 0.001) between ischemic and remote myocardial regions after adjusting for biological sex and slice location. Analysis of fMBV as a predictor of impaired myocardial contractility using receiver operating characteristics showed an area under the curve of 0.89 (95% confidence interval [CI] 0.80, 0.95). An MRI-fMBV threshold of 9.60% has a specificity of 90.0% (95% CI 76.3, 97.2) and a sensitivity of 72.5% (95% CI 56.1, 83.4) for prediction of impaired myocardial contractility., Conclusions: Model-fitted fMBV derived from ferumoxytol-enhanced MRI can distinguish regions of ischemia from remote myocardium in a swine model of myocardial hypoperfusion., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: PSMA-TO-1 ("Tumor-Optimized-1") is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68 Ga and 177 Lu, and the survival after treatment with 225 Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177 Lu-PSMA-TO1/-617 in prostate cancer patients., Methods: First, PET images of 68 Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177 Lu-PSMA-617 or 177 Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225 Ac-PSMA-617, 225 Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177 Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations., Results: Tumor uptake measured by PET imaging of 68 Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177 Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225 Ac-PSMA-TO-1 survived longer than those treated with 225 Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p < 0.0001). Kidney, salivary gland, bone marrow and mean ± SD tumor dose coefficients (Gy/GBq) for 177 Lu-PSMA-TO-1 in patients #01/#02/#03 were 2.5/2.4/3.0, 1.0/2.5/2.3, 0.14/0.11/0.10 and 0.42 ± 0.03/4.45 ± 0.07/1.8 ± 0.57, respectively., Conclusions: PSMA-TO-1 tumor uptake tended to be greater than that of PSMA-617 in both preclinical and clinical settings. Mice treated with 225 Ac-PSMA-TO-1 conferred a significant survival benefit compared to 225 Ac-PSMA-617 despite the accompanying increased kidney uptake. In humans, PSMA-TO-1 dosimetry estimates suggest increased tumor absorbed doses; however, the kidneys, salivary glands and bone marrow are also exposed to higher radiation doses. Thus, additional preclinical studies are needed before further clinical use., (© 2022. The Author(s).)

Background: The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes., Methods: A Monte Carlo simulation model of an 241 Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the 241 Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF., Results: The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations., Conclusion: Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry., (© 2022. The Author(s).)

The purpose of this analysis was to report the safety evaluation of 177 Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177 Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results : The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177 Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177 Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion: 177 Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177 Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The objective of this study was to determine prospectively the efficacy profile of 2 activity regimens of 177 Lu-PSMA therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC): 6.0 vs. 7.4 GBq. Methods: RESIST-PC (NCT03042312) was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA expression by PSMA PET were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq) and received up to 4 cycles every 8 wk. The primary endpoint was the efficacy of 177 Lu-PSMA measured by the prostate-specific antigen (PSA) response rate (RR) after 2 cycles (≥50% decline from baseline). Secondary endpoints included the PSA RR (≥50% decline) at any time (best response), and overall survival (OS). Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. We report here the efficacy of the University of California Los Angeles cohort results only ( n  = 43). The PSA RRs after 2 cycles and at any time were 11/40 (28%, 95% CI 15-44), 6/13 (46%, 95% CI 19-75), and 5/27 (19%, 95% CI 6-38), and 16/43 (37%, 95% CI 23-53), 7/14 (50%, 95% CI 23-77), and 9/29 (31%, 95% CI 15-51) in the whole cohort, the 6.0-GBq group, and the 7.4-GBq group, respectively ( P  = 0.12 and P  = 0.31). The median OS was 14.0 mo (95% CI 10.1-17.9), 15.8 (95% CI 11.8-19.4), and 13.5 (95% CI 10.0-17.0) in the whole cohort, the 6.0-GBq group, and the 7.4 GBq group, respectively ( P  = 0.87). OS was longer in patients who experienced a PSA decline ≥ 50% at any time than in those who did not: median, 20.8 versus 10.8 mo ( P  = 0.005). Conclusion: In this prospective phase 2 trial of 177 Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177 Lu-PSMA appeared to be favorable and comparable with both activity regimens (6.0 vs. 7.4 GBq). Results justify confirmation with real-world data matched-pair analysis and further clinical trials to refine and optimize the 177 Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT because of the high salivary gland uptake of PSMA radioligands. Here, we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using 68 Ga-PSMA-11 PET imaging. Methods: Sixteen men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ("swishing") arms. Each subject underwent 2 68 Ga-PSMA-11 PET/CT scans within 14 d under baseline and MSG conditions. The salivary glands and whole-body tumor lesions were segmented using qPSMA software. We quantified tracer uptake via SUV mean and SUV max and compared parameters within each patient. Results: For the oral ingestion arm, salivary gland SUV mean and SUV max decreased on average from the control scan to the MSG scan by 45% ± 15% ( P = 0.004) and 53% ± 11% ( P < 0.001), respectively. Tumor lesion SUV mean and SUV max also decreased by 38% (interquartile range, -67% to -33%) and -52% (interquartile range, -70% to -49%), respectively ( P = 0.018). Swishing had no significant effect on 68 Ga-PSMA-11 accumulation in normal organs or tumor lesions. Conclusion: Oral ingestion but not topical application of MSG reduced 68 Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined; therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

99m Tc-PSMA I&S is a prostate-specific membrane antigen (PSMA) tracer that can be used for planar and SPECT/CT γ-imaging and radioguided surgery. The primary aim of this study was to estimate the dosimetry of 99m Tc-PSMA I&S using a hybrid method (sequential γ-planar imaging and 1 single SPECT/CT) in healthy volunteers. The secondary aim was to depict the tracer biodistribution and tumor-to-background ratios (TBRs) in patients with prostate cancer (PCa). Methods: Dosimetry of 99m Tc-PSMA I&S was investigated in 4 healthy volunteers. Whole-body planar imaging was acquired at 1, 2, 3, 6, and 24 h and SPECT/CT at 6 h after tracer injection. Contours of organs were drawn on all acquisitions to determine organ activity at each time point. Absorbed dose was estimated using 2 methods: independent curve-fitting manual method (Levenberg-Marquardt-based algorithm using dose factors from RAdiation Dose Assessment Resource [RADAR] website) and OLINDA/EXM software (version 2.0; HERMES Medical Solutions). Biodistribution of 99m Tc-PSMA I&S was assessed in 10 patients with PCa on SPECT/CT images at 6 h. Tumor uptake (SUV max ), and TBR (tumor SUV max /background organ SUV mean ) using muscle (T/M), bladder (T/B), and intestine (T/I) as background organs were determined. Results: The mean injected activity of 99m Tc-PSMA I&S was 717 MBq (range: 562-828 MBq). No adverse events related to the injection of 99m Tc-PSMA I&S were reported. The average radiation effective dose was 0.0055 mSv/MBq with the RADAR manual method and 0.0052 mSv/MBq with OLINDA/EXM. Total body effective dose ranged between 3.33-4.42 and 3.11-4.23 mSv, respectively. All PCa patients showed high tracer uptake in primary and metastatic lesions with T/M, T/B, and T/I ranging from 5.29-110, 0.11-7.02, and 0.96-16.30, respectively. Conclusion: Effective doses of 99m Tc-PSMA I&S were comparable to those known for most of the 99m Tc tracers and was lower than for the 68 Ga-labeled and 18 F-labeled agents. 99m Tc-PSMA I&S SPECT/CT showed high TBR in PCa patients. This study can provide required data for translation and approval of 99m Tc-PSMA I&S by regulatory agencies., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA RLT. Methods: Therapeutic efficacy of PSMA RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53 -/- tumor-bearing nonobese diabetic scid γ-mice. Two days after RLT, the proteome and phosphoproteome were analyzed by mass spectrometry. Results: PSMA RLT significantly improved disease control in a dose-dependent manner. Proteome and phosphoproteome datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, phosphatidylinositol-3-kinase/AKT, and MYC signaling. C4-2 TP53 -/- tumors were less sensitive to PSMA RLT than were parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusion: We identified signaling alterations that may mediate resistance to PSMA RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Regular and precise inspection of the realization of the local nuclear medicine standard operation procedures (SOPs) is very complex and time-consuming, especially when large amount of patient data is obtained from a wide scale of different scan procedures on a daily basis. DICOM metadata comprise a complete set of data related to the patient and the imaging procedure, and consequently all information necessary to evaluate the compliance with the actual SOP., Methods: Q-Bot, an automatic DICOM metadata monitoring tool which is capable to verify SOP conformities, was tested for 11 months at two nuclear medicine departments. Relevant parameters, such as patient ID, patient mass and height, injected activity, and uptake time, were investigated in the case of adult 18 F-FDG whole-body PET/CT and 99m Tc-MDP gamma camera bone scans on a daily basis. Q-Bot automatically inspected the actual SOP compliance of these relevant DICOM parameters. Q-Bot graphical user interface (GUI) provided a summary of the outliers in a table format to be investigated by a dedicated technologist. In addition, information related to the error handling was also collected for retrospective analysis of long-term tendencies., Results: In total, 6702 PET/CT and 2502 gamma camera scans were inspected, from which 8581 were confirmed as valid patient study without errors. Discrepancies related to the lack of a parameter, not appropriate format, or improper scan procedures were found in 623 cases, and 156 out of these were corrected before the medical reading and reporting. SOP non-conformities explored with Q-Bot were found to be non-correctable in 467 cases. Systematic errors to our practice turned out to be the manual radiopharmaceutical injection, the allowance to use both SI and non-SI units, and the clear definition of decimal point symbol to use., Conclusion: The daily evaluation of Q-Bot results provided early detection of errors and consequently ensured the minimization of error propagation. Integration of a QM software that inspects protocol compliance at a nuclear medicine department provides significant support to detect non-conformities for technologists, and much higher confidence in image quality for physicians.

Purpose: Radioimmunotherapy uses tumor-specific antibodies to deliver therapeutic radionuclides, but hematological toxicity due to the long serum half-life of intact antibodies remains a challenge. We evaluated a smaller antibody fragment, the minibody, with faster kinetics and a potentially improved therapeutic index., Procedures: The anti-prostate stem cell antigen (PSCA) minibody (A11 Mb) was radiolabeled with iodine-124 ([ 124 I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([ 89 Zr]Zr-DFO-A11 Mb) for surrogate immunoPET to profile pharmacokinetics in a human prostate cancer xenograft model. Subsequently, minibodies labeled with two therapeutic beta emitters, directly iodinated [ 131 I]I-A11 Mb (non-residualizing) and 177 Lu chelated using DTPA ([ 177 Lu]Lu-DTPA-A11 Mb) (residualizing), were compared for in vitro antigen-specific cytotoxicity. Full biodistribution studies (in 22Rv1-PSCA tumor bearing and hPSCA knock-in mice) were conducted for dosimetry calculations. Finally, the lead candidate [ 131 I]I-A11 Mb was evaluated in a radioimmunotherapy experiment. Escalating single doses (3.7, 11, or 37 MBq) and saline control were administered to 22Rv1-PSCA tumor bearing mice and anti-tumor effects (tumor volume) and toxicity (body weight) were monitored., Results: Minibodies radiolabeled with therapeutic beta emitters [ 131 I]I-A11 Mb and [ 177 Lu]Lu-DTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [ 89 Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [ 124 I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [ 131 I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone marrow). For [ 177 Lu]Lu-DTPA-A11 Mb, the kidneys would be dose-limiting, and the maximum tolerated activity (7.4 MBq) was not predicted to deliver an effective radiation dose to tumor. Radioimmunotherapy with a single dose of [ 131 I]I-A11 Mb showed dose-dependent tumor inhibition with minimal off-target toxicity and improved median survival (19 and 24 days, P < 0.001) compared with untreated mice (12 days)., Conclusions: These findings show the potential of the anti-PSCA minibody for targeted radioimmunotherapy with minimal toxicity, and the application of immunoPET and dosimetry for personalized treatment.

Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer 68 Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of 68 Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial 68 Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUV max /organ SUV mean ). Results: At all time points, average SUV max was highest in the liver. Tumor and organ SUV mean decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04 mSv/MBq). The average effective total-body dose was 7.80E-03 mSv/MBq. Conclusion: 68 Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of 68 Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

225 Ac-PSMA-617 targeted-therapy has demonstrated efficacy in 75-85% of patients; however, responses are not durable. We aimed to establish translatable mouse models of disseminated prostate cancer (PCa) to evaluate effectiveness of 225 Ac-PSMA-617 at various disease stages. Methods : C4-2, C4-2B, or 22Rv1 cells were injected into the left ventricle of male NSG mice. Disease progression was monitored using bioluminescence imaging (BLI). For treatment, mice were injected with 40 kBq 225 Ac-PSMA-617 at one (early treatment cohort) or three weeks (late treatment cohort) post-inoculation. Treatment efficacy was monitored by BLI of whole-body tumor burden. Mice were sacrificed based on body conditioning score. Results : C4-2 cells yielded metastases in liver, lungs, spleen, stomach, bones, and brain - achieving a clinically relevant model of widespread metastatic disease. The disease burden in the early treatment cohort was stable over 27 weeks in 5/9 mice and progressive in 4/9 mice. These mice were sacrificed due to brain metastases. Median survival of the late treatment cohort was superior to controls (13 vs. 7 weeks; p<0.0001) but inferior to that in the early treatment cohort (13 vs. 27 weeks; p<0.001). Late cohort mice succumbed to extensive liver involvement. The 22Rv1 and C4-2B systemic models were not used for treatment due to high kidney metastatic burden or low take rate, respectively. Conclusion : C4-2 cells reproduced metastatic cancer spread most relevantly. Early treatment with 225 Ac-PSMA-617 prevented liver metastases and led to significant survival benefit. Late treatment improved survival without reducing tumor burden in the liver, the main site of metastasis. The current findings suggest that early 225 Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic PCa., Competing Interests: Competing Interests: JC and CR are co-founders and hold equity in Sofie Biosciences and Trethera Therapeutics. Intellectual property has been patented by the University of California and has been licensed to Sofie Biosciences and Trethera Therapeutics. This intellectual property was not used in the current study. No other potential conflict of interest relevant to this article was reported., (© The author(s).)

The objectives of this study were to evaluate radiation dosimetry, biodistribution, human safety, and tolerability of 18 F-labeled flurpiridaz (Flurpiridaz) in normal subjects undergoing rest and separate-day exercise or adenosine pharmacological stress PET imaging., Methods: 12 normal subjects were injected with 58.5 to 121 MBq (1.58 to 3.27 mCi) of Flurpiridaz intravenously at rest on Day 1 and 57 to 171 MBq (1.54 to 4.61 mCi) during stress on Day 2. Sequential whole-body imaging was performed for 5 hours. Blood samples were collected for up to 8 hours., Results: The heart wall received the largest mean absorbed dose with both exercise and adenosine stresses. The mean effective dose was 0.054 rem/mCi (0.015 mSv/MBq) with exercise and 0.069 rem/mCi (0.019 mSv/MBq) with adenosine pharmacological stress. The maximum dose that may be administered without exceeding 1 rem (10 mSv) effective dose was 19 mCi (685 MBq) for exercise and 15 mCi (539 MBq) for adenosine pharmacological stress. There were no drug-related adverse events, and the tracer was well tolerated in all subjects., Conclusion: Based on radiation dosimetry, biodistribution, and safety observations, 18 F-labeled flurpiridaz is found suitable for clinical PET myocardial perfusion imaging in conjunction with either exercise or pharmacological stress testing.

Background: National Comprehensive Cancer Network guidelines consider 18 F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18 F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL)., Methods: This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18 F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete., Findings: Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18 F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18 F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078)., Interpretation: With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Performing PET imaging during ongoing radionuclide therapy can be a promising method to follow tumor response in vivo. However, the high therapeutic activity can interfere with the PET camera performance and degrade both image quality and quantitative capabilities. As a solution, low-energy photon emissions from the therapeutic radionuclide can be highly attenuated, still allowing sufficient detection of annihilation photons in coincidence. Methods: Hollow Rose metal cylinders with walls 2-4 mm thick were used to shield a 22 Na point source and a uniform phantom filled with 18 F as they were imaged on a preclinical PET camera with increasing activities of 177 Lu. A mouse with a subcutaneous tumor was injected with 18 F-FDG and imaged with an additional 120 MBq of 177 Lu and repeated with shields surrounding the animal. Results: The addition of 177 Lu to the volume imaged continuously degraded the image quality with increasing activity. The image quality was improved when shielding was introduced. The shields showed a high ability to produce stable and reproducible results for both spatial resolution and quantification of up to 120 MBq of 177 Lu activity (maximum activity tested). Conclusion: Without shielding, the activity quantification will be inaccurate for time points at which therapeutic activities are high. The suggested method shows that the shields reduce the noise induced by the 177 Lu and therefore enable longitudinal quantitative intratherapeutic imaging studies., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

The aim of this work was to develop a novel phantom that supports the construction of highly reproducible phantoms with arbitrary activity distributions for PET imaging. It could offer a methodology for answering questions related to texture measurements in PET imaging. The basic idea is to move a point source on a 3-D trajectory in the field of view, while continuously acquiring data. The reconstruction results in a 3-D activity concentration map according to the pathway of the point source. A 22Na calibration point source was attached to a high precision robotic arm system, where the 3-D movement was software controlled. 3-D activity distributions of a homogeneous cube, a sphere, a spherical shell and a heart shape were simulated. These distributions were used to measure uniformity and to characterize reproducibility. Two potential applications using the lesion simulation method are presented: evaluation in changes of textural properties related to the position in the PET field of view; scanner comparison based on visual and quantitative evaluation of texture features. A lesion with volume of 50x50x50 mm3 can be simulated during approximately 1 hour. The reproducibility of the movement was found to be >99%. The coefficients of variation of the voxels within a simulated homogeneous cube was 2.34%. Based on 5 consecutive and independent measurements of a 36 mm diameter hot sphere, the coefficient of variation of the mean activity concentration was 0.68%. We obtained up to 18% differences within the values of investigated textural indexes, when measuring a lesion in different radial positions of the PET field of view. In comparison of two different human PET scanners the percentage differences between heterogeneity parameters were in the range of 5-55%. After harmonizing the voxel sizes this range reduced to 2-16%. The general activity distributions provided by the two different vendor show high similarity visually. For the demonstration of the flexibility of this method, the same pattern was also simulated on a small animal PET scanner giving similar results, both quantitatively and visually. 3-D motion of a point source in the PET field of view is capable to create an irregular shaped activity distribution with high reproducibility., Competing Interests: A.F, A.K.K, F.N, I.G are employed by ScanoMed Ltd. There are no patents, products in development, or marketed products to declare. This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials.

Purpose: The aim of this study was to examine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting subsequent rates of functional and cognitive decline among subjects considered cognitively normal (CN) or clinically diagnosed with mild cognitive impairment (MCI)., Methods: Analyses of 276 subjects, 92 CN subjects and 184 with MCI, who were enrolled in the Alzheimer's Disease Neuroimaging Initiative, were conducted. Functional decline was assessed using scores on the Functional Activities Questionnaire (FAQ) obtained over a period of 36 months, while cognitive decline was determined using the Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) scores. PET images were analyzed using clinically routine brain quantification software. A dementia prognosis index (DPI), derived from a ratio of uptake values in regions of interest known to be hypometabolic in Alzheimer's disease to regions known to be stable, was generated for each baseline FDG-PET scan. The DPI was correlated with change in scores on the neuropsychological examinations to examine the predictive value of baseline FDG-PET., Results: DPI powerfully predicted rate of functional decline among MCI patients (t = 5.75, p < 1.0E-8) and pooled N + MCI patient groups (t = 7.02, p < 1.0E-11). Rate of cognitive decline on MMSE was also predicted by the DPI among MCI (t = 6.96, p < 1.0E-10) and pooled N + MCI (t = 8.78, p < 5.0E-16). Rate of cognitive decline on ADAS-cog was powerfully predicted by the DPI alone among N (p < 0.001), MCI (t = 6.46, p < 1.0E-9) and for pooled N + MCI (t = 8.85, p = 1.1E-16)., Conclusions: These findings suggest that an index, derivable from automated regional analysis of brain PET scans, can be used to help predict rates of functional and cognitive deterioration in the years following baseline PET.

PET may provide important information on the response during radiopharmaceutical therapy (RPT). Emission of radiation from the RPT radionuclide may disturb coincidence detection and impair image resolution. In this study, we tested the feasibility of performing intratherapeutic PET on 3 preclinical PET systems., Methods: Using 22 Na point sources and phantoms filled with 18 F, as well as a phantom filled with either 99m Tc or 177 Lu, we evaluated the coincidence counting rate and spatial resolution when both a PET and a therapeutic radionuclide were in the PET system. Because 99m Tc has a suitable half-life and is easy obtainable, we used it as a substitute for a generic therapeutic radionuclide., Results: High activities of 99m Tc deteriorated the coincidence counting rate from the 18 F-filled phantom and the 22 Na point source on all 3 systems. The counting rate could be corrected to a high degree on one of the systems by its dead-time correction. Spatial resolution was degraded at high 99m Tc activities for all systems. On one of the systems, 177 Lu increased the coincidence counting rate and slightly affected the spatial resolution. The results for high 177 Lu activities were similar to those for 99m Tc., Conclusion: Intratherapeutic imaging might be a feasible method of studying the response to RPT. However, some sensitive preclinical PET systems, unable to handle high counting rates, will have count losses and may also introduce image artifacts., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Textural analysis might give new insights into the quantitative characterization of metabolically active tumors. More than thirty textural parameters have been investigated in former F18-FDG studies already. The purpose of the paper is to declare basic requirements as a selection strategy to identify the most appropriate heterogeneity parameters to measure textural features. Our predefined requirements were: a reliable heterogeneity parameter has to be volume independent, reproducible, and suitable for expressing quantitatively the degree of heterogeneity. Based on this criteria, we compared various suggested measures of homogeneity. A homogeneous cylindrical phantom was measured on three different PET/CT scanners using the commonly used protocol. In addition, a custom-made inhomogeneous tumor insert placed into the NEMA image quality phantom was imaged with a set of acquisition times and several different reconstruction protocols. PET data of 65 patients with proven lung lesions were retrospectively analyzed as well. Four heterogeneity parameters out of 27 were found as the most attractive ones to characterize the textural properties of metabolically active tumors in FDG PET images. These four parameters included Entropy, Contrast, Correlation, and Coefficient of Variation. These parameters were independent of delineated tumor volume (bigger than 25-30 ml), provided reproducible values (relative standard deviation< 10%), and showed high sensitivity to changes in heterogeneity. Phantom measurements are a viable way to test the reliability of heterogeneity parameters that would be of interest to nuclear imaging clinicians., Competing Interests: The authors have declared that no competing interests exist.

Unlabelled: We recently completed construction of a small-animal PET system-the MiniPET-3-that uses state-of-the-art silicon photomultiplier (SiPM) photosensors, making possible dual-modality imaging with MRI. In this article, we compare the MiniPET-3 with the MiniPET-2, a system with the same crystal geometry but conventional photomultiplier tubes (PMTs)., Methods: The standard measurements proposed by the National Electrical Manufacturers Association NU 4 protocols were performed on both systems. These measurements included spatial resolution, system sensitivity, energy resolution, counting rate performance, scatter fraction, spillover ratio for air and water, recovery coefficient, and image uniformity. The energy windows were set to 350-650 keV on the MiniPET-2 and 360-662 keV on the MiniPET-3., Results: Spatial resolution was approximately 17% better on average for the MiniPET-3 than the MiniPET-2. The systems performed similarly in terms of peak absolute sensitivity (∼1.37%), spillover ratio for air (∼0.15), spillover ratio for water (∼0.25), and recovery coefficient (∼0.33, 0.59, 0.81, 0.89, and 0.94). Uniformity was 5.59% for the MiniPET-2 and 6.49% for the MiniPET-3. Minor differences were found in scatter fraction. With the ratlike phantom, the peak noise-equivalent counting rate was 14 kcps on the MiniPET-2 but 24 kcps on the MiniPET-3. However, with the mouselike phantom, these values were 55 and 91 kcps, respectively. The optimal coincidence time window was 6 ns for the MiniPET-2 and 8 ns for the MiniPET-3., Conclusion: Images obtained with the SiPM-based MiniPET-3 small-animal PET system are similar in quality to those obtained with the conventional PMT-based MiniPET-2., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Monte Carlo simulation provides a valuable tool in performance assessment and optimization of system design parameters for PET scanners. SimSET is a popular Monte Carlo simulation toolkit that features fast simulation time, as well as variance reduction tools to further enhance computational efficiency. However, SimSET has lacked the ability to simulate block detectors until its most recent release. Our goal is to validate new features of SimSET by developing a simulation model of the Siemens Biograph mCT PET scanner and comparing the results to a simulation model developed in the GATE simulation suite and to experimental results. We used the NEMA NU-2 2007 scatter fraction, count rates, and spatial resolution protocols to validate the SimSET simulation model and its new features. The SimSET model overestimated the experimental results of the count rate tests by 11-23% and the spatial resolution test by 13-28%, which is comparable to previous validation studies of other PET scanners in the literature. The difference between the SimSET and GATE simulation was approximately 4-8% for the count rate test and approximately 3-11% for the spatial resolution test. In terms of computational time, SimSET performed simulations approximately 11 times faster than GATE simulations. The new block detector model in SimSET offers a fast and reasonably accurate simulation toolkit for PET imaging applications.

Purpose: The most commonly used technology currently used for autoradiography is storage phosphor screens, which has many benefits such as a large field of view but lacks particle-counting detection of the time and energy of each detected radionuclide decay. A number of alternative designs, using either solid state or scintillator detectors, have been developed to address these issues. The aim of this study is to characterize the imaging performance of one such instrument, a double-sided silicon strip detector (DSSD) system for digital autoradiography. A novel aspect of this work is that the instrument, in contrast to previous prototype systems using the same detector type, provides the ability for user accessible imaging with higher throughput. Studies were performed to compare its spatial resolution to that of storage phosphor screens and test the implementation of multiradionuclide ex vivo imaging in a mouse preclinical animal study., Methods: Detector background counts were determined by measuring a nonradioactive sample slide for 52 h. Energy spectra and detection efficiency were measured for seven commonly used radionuclides under representative conditions for tissue imaging. System dead time was measured by imaging (18)F samples of at least 5 kBq and studying the changes in count rate over time. A line source of (58)Co was manufactured by irradiating a 10 μm nickel wire with fast neutrons in a research reactor. Samples of this wire were imaged in both the DSSD and storage phosphor screen systems and the full width at half maximum (FWHM) measured for the line profiles. Multiradionuclide imaging was employed in a two animal study to examine the intratumoral distribution of a (125)I-labeled monoclonal antibody and a (131)I-labeled engineered fragment (diabody) injected in the same mouse, both targeting carcinoembryonic antigen., Results: Detector background was 1.81 × 10(-6) counts per second per 50 × 50 μm pixel. Energy spectra and detection efficiency were successfully measured for seven radionuclides. The system dead time was measured to be 59 μs, and FWHM for a (58)Co line source was 154 ± 14 μm for the DSSD system and 343 ± 15 μm for the storage phosphor system. Separation of the contributions from (125)I and (131)I was performed on autoradiography images of tumor sections., Conclusions: This study has shown that a DSSD system can be beneficially applied for digital autoradiography with simultaneous multiradionuclide imaging capability. The system has a low background signal, ability to image both low and high activity samples, and a good energy resolution.

Background and Purpose: To quantify tumor volume coverage and excess normal tissue coverage using margin expansions of mobile target internal target volumes (ITVs) in the lung., Materials and Methods: FDG-PET list-mode data were acquired for four spheres ranging from 1 to 4 cm as they underwent 1D motion based on four patient breathing trajectories. Both ungated PET images and PET maximum intensity projections (PET-MIPs) were examined. Amplitude-based gating was performed on sequential list-mode files of varying signal-to-background ratios to generate PET-MIPs. ITVs were first post-processed using either a Gaussian filter or a custom two-step module, and then segmented by applying a gradient-based watershed algorithm. Uniform and non-uniform 1 mm margins were added to segmented ITVs until complete target coverage was achieved., Results: PET-MIPs required smaller uniform margins (4.7 vs. 11.3 mm) than ungated PET, with correspondingly smaller over-coverage volumes (OCVs). Non-uniform margins consistently resulted in smaller OCVs when compared to uniform margins. PET-MIPs and ungated PET had comparable OCVs with non-uniform margins, but PET-MIPs required smaller longitudinal margins (4.7 vs. 8.5 mm). Non-uniform margins were independent of sphere size., Conclusions: Gated PET-MIP images and non-uniform margins result in more accurate ITV delineation while reducing normal tissue coverage.

Unlabelled: Absolute quantitation of myocardial blood flow (MBF) by PET is an established method of analyzing coronary artery disease (CAD) but subject to the various shortcomings of available radiotracers. Flurpiridaz F 18 is a novel PET radiotracer that exhibits properties of an ideal tracer., Methods: A new absolute perfusion quantitation method with flurpiridaz was developed, taking advantage of the early kinetics and high first-pass extraction by the myocardium of this radiotracer, and the first-in-human measurements of MBF performed in 7 healthy subjects and 8 patients with documented CAD. PET images with time-activity curves were acquired at rest and during adenosine stress., Results: In healthy subjects, regional MBF between coronary artery territories did not differ significantly, leading to a mean global MBF of 0.73 mL/min/g at rest and 2.53 mL/min/g during stress, with a mean global myocardial flow reserve (MFR) of 3.70. CAD vascular territories with <50% stenosis demonstrated a mean MBF of 0.73 at rest and 2.02 during stress, leading to a mean MFR of 2.97. CAD vascular territories with ≥50% stenosis exhibited a mean MBF of 0.86 at rest and 1.43 during stress, leading to a mean MFR of 1.86. Differences in stress MBF and MFR between normal and CAD territories, as well as between <50% and ≥50% stenosis vascular territories, were significant (P < 0.01)., Conclusion: Absolute quantitation of MBF in humans with the novel PET radiotracer flurpiridaz is feasible over a wide range of cardiac flow in the presence or absence of stress-inducible myocardial ischemia. The significant decrease in stress MBF and ensuing MFR in CAD territories allows a clear distinction between vascular territories exhibiting stress-inducible myocardial ischemia and those with normal perfusion., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method's performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.

The contrast recovery coefficients (CRC) were evaluated for five different small animal PET scanners: GE Explore Vista, Genisys4, MiniPET-2, nanoScan PC and Siemens Inveon. The NEMA NU-4 2008 performance test with the suggested image quality phantom (NU4IQ) does not allow the determination of the CRC values for the hot regions in the phantom. This drawback of NU4IQ phantom motivated us to develop a new method for this purpose. The method includes special acquisition and reconstruction protocols using the original phantom, and results in an artificially merged image enabling the evaluation of CRC values. An advantageous feature of this method is that it stops the cold wall effect from distorting the CRC calculation. Our suggested protocol results in a set of CRC values contributing to the characterization of small animal PET scanners. GATE simulations were also performed to validate the new method and verify the evaluated CRC values. We also demonstrated that the numerical values of this parameter depend on the actual object contrast of the hot region(s) and this mainly comes from the spillover effect. This effect was also studied while analysing the background activity level around the hot rods. We revealed that the calculated background mean values depended on the target contrast in a scanner specific manner. Performing the artificially merged imaging procedure and additional simulations using the micro hollow sphere (MHS) phantom geometry, we also proved that the inactive wall around the hot spheres can have a remarkable impact on the calculated CRC. In conclusion, we have shown that the proposed artificial merging procedure and the commonly used NU4IQ phantom prescribed by the NEMA NU-4 can easily deliver reliable CRC data otherwise unavailable for the NU4IQ phantom in the conventional protocol or the MHS phantom.

Purpose: In this study, kinetic parameters of the cellular proliferation tracer (18)F-3'-deoxy-3'-fluoro-L-thymidine (FLT) and the amino acid probe 3,4-dihydroxy-6-(18)F-fluoro-L-phenylalanine (FDOPA) were measured before and early after the start of therapy, and were used to predict the overall survival (OS) of patients with recurrent malignant glioma using multiple linear regression (MLR) analysis., Methods: High-grade recurrent brain tumors in 21 patients (11 men and 10 women, age range 26 - 76 years) were investigated. Each patient had three dynamic PET studies with each probe: at baseline and after 2 and 6 weeks from the start of treatment. Treatment consisted of biweekly cycles of bevacizumab (an angiogenesis inhibitor) and irinotecan (a chemotherapeutic agent). For each study, about 3.5 mCi of FLT (or FDOPA) was administered intravenously and dynamic PET images were acquired for 1 h (or 35 min for FDOPA). A total of 126 PET scans were analyzed. A three-compartment, two-tissue model was applied to estimate tumor FLT and FDOPA kinetic rate constants using a metabolite- and partial volume-corrected input function. MLR analysis was used to model OS as a function of FLT and FDOPA kinetic parameters for each of the three studies as well as their relative changes between studies. An exhaustive search of MLR models using three or fewer predictor variables was performed to find the best models., Results: Kinetic parameters from FLT were more predictive of OS than those from FDOPA. The three-predictor MLR model derived using information from both probes (adjusted R(2) = 0.83) fitted the OS data better than that derived using information from FDOPA alone (adjusted R(2) = 0.41), but was only marginally different from that derived using information from FLT alone (adjusted R(2) = 0.82). Standardized uptake values (either from FLT alone, FDOPA alone, or both together) gave inferior predictive results (best adjusted R(2) = 0.25)., Conclusion: For recurrent malignant glioma treated with bevacizumab and irinotecan, FLT kinetic parameters obtained early after the start of treatment (absolute values and their associated changes) can provide sufficient information to predict OS with reasonable confidence using MLR. The slight increase in accuracy for predicting OS with a combination of FLT and FDOPA PET information may not warrant the additional acquisition of FDOPA PET for therapy monitoring in patients with recurrent glioma.

Time-of-flight (TOF) information improves the signal-to-noise ratio in positron emission tomography (PET). The computation cost in processing TOF-PET sinograms is substantially higher than for nonTOF data because the data in each line of response is divided among multiple TOF bins. This additional cost has motivated research into methods for rebinning TOF data into lower dimensional representations that exploit redundancies inherent in TOF data. We have previously developed approximate Fourier methods that rebin TOF data into either three-dimensional (3D) nonTOF or 2D nonTOF formats. We refer to these methods respectively as FORET-3D and FORET-2D. Here we describe maximum a posteriori (MAP) estimators for use with FORET rebinned data. We first derive approximate expressions for the variance of the rebinned data. We then use these results to rescale the data so that the variance and mean are approximately equal allowing us to use the Poisson likelihood model for MAP reconstruction. MAP reconstruction from these rebinned data uses a system matrix in which the detector response model accounts for the effects of rebinning. Using these methods we compare the performance of FORET-2D and 3D with TOF and nonTOF reconstructions using phantom and clinical data. Our phantom results show a small loss in contrast recovery at matched noise levels using FORET compared to reconstruction from the original TOF data. Clinical examples show FORET images that are qualitatively similar to those obtained from the original TOF-PET data but with a small increase in variance at matched resolution. Reconstruction time is reduced by a factor of 5 and 30 using FORET3D+MAP and FORET2D+MAP respectively compared to 3D TOF MAP, which makes these methods attractive for clinical applications.

Purpose: To quantitatively compare the accuracy of tumor volume segmentation in amplitude-based and phase-based respiratory gating algorithms in respiratory-correlated positron emission tomography (PET)., Methods and Materials: List-mode fluorodeoxyglucose-PET data was acquired for 10 patients with a total of 12 fluorodeoxyglucose-avid tumors and 9 lymph nodes. Additionally, a phantom experiment was performed in which 4 plastic butyrate spheres with inner diameters ranging from 1 to 4 cm were imaged as they underwent 1-dimensional motion based on 2 measured patient breathing trajectories. PET list-mode data were gated into 8 bins using 2 amplitude-based (equal amplitude bins [A1] and equal counts per bin [A2]) and 2 temporal phase-based gating algorithms. Gated images were segmented using a commercially available gradient-based technique and a fixed 40% threshold of maximum uptake. Internal target volumes (ITVs) were generated by taking the union of all 8 contours per gated image. Segmented phantom ITVs were compared with their respective ground-truth ITVs, defined as the volume subtended by the tumor model positions covering 99% of breathing amplitude. Superior-inferior distances between sphere centroids in the end-inhale and end-exhale phases were also calculated., Results: Tumor ITVs from amplitude-based methods were significantly larger than those from temporal-based techniques (P=.002). For lymph nodes, A2 resulted in ITVs that were significantly larger than either of the temporal-based techniques (P<.0323). A1 produced the largest and most accurate ITVs for spheres with diameters of ≥2 cm (P=.002). No significant difference was shown between algorithms in the 1-cm sphere data set. For phantom spheres, amplitude-based methods recovered an average of 9.5% more motion displacement than temporal-based methods under regular breathing conditions and an average of 45.7% more in the presence of baseline drift (P<.001)., Conclusions: Target volumes in images generated from amplitude-based gating are larger and more accurate, at levels that are potentially clinically significant, compared with those from temporal phase-based gating., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: The Genisys4 is a small bench-top preclinical PET scanner designed to enable imaging in biology, biochemistry, and pharmacology laboratories and imaging centers. Here, we compare its performance with that of a well-established preclinical PET scanner., Methods: Subcutaneous and lung tumor xenografts were used to compare lesion detectability and treatment responses to chemotherapy (gemcitabine) using (18)F-FDG PET. The size of subcutaneous xenografts (L1210 and L1210-10K leukemia cells) and lung metastases (B-16 melanoma cells) was measured on small-animal CT images. Tumor (18)F-FDG uptake was expressed as percentage injected dose per gram. Using list-mode data, serial images of the left ventricular blood pool were used to generate time-activity curves., Results: Subcutaneous xenografts (range, 4-12 mm; mean ± SD, 6.1 ± 1.7 mm) and lung metastases (range, 1-5 mm; mean, 2.1 ± 1.2 mm) were detected equally well with both scanners. Tumor (18)F-FDG uptake measured with both scanners was highly correlated for subcutaneous xenografts (r(2) = 0.93) and lung metastases (r(2) = 0.83). The new Genisys4 scanner and the established scanner provided comparable treatment response information (r(2) = 0.93). Dynamic imaging sequences permitted the generation of left ventricular blood-pool time-activity curves with both scanners., Conclusion: Using subcutaneous and lung xenografts, a novel and an established preclinical PET scanner provided equivalent information with regard to lesion detection, tumor (18)F-FDG uptake, tumor response to treatment, and generation of time-activity curves. Thus, the Genisys4 provides a small, efficient bench-top preclinical PET alternative for quantitatively studying murine tumor models in biology, biochemistry, and pharmacology laboratories and preclinical imaging centers.

Purpose: The aim of the study was to determine whether glucose uptake in viable myocardium of ischemic cardiomyopathy patients depends on rest myocardial blood flow (MBF) and the residual myocardial flow reserve (MFR)., Methods: Thirty-six patients with ischemic cardiomyopathy (left ventricular ejection fraction 25 ± 10 %) were studied with (13)N-ammonia and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Twenty age-matched normals served as controls. Regional MBF was determined at rest and during dipyridamole hyperemia and regional FDG extraction was estimated from regional FDG to (13)N-ammonia activity ratios., Results: Rest MBF was reduced in viable (0.42 ± 0.18 ml/min per g) and nonviable regions (0.32 ± 0.09 ml/min per g) relative to remote regions (0.68 ± 0.23 ml/min per g, p < 0.001) and to normals (0.63 ± 0.13 ml/min per g). Dipyridamole raised MBFs in controls, remote, viable, and nonviable regions. MBFs at rest (p < 0.05) and stress (p < 0.05) in viable regions were significantly higher than that in nonviable regions, while MFRs did not differ significantly (p > 0.05). Compared to MFR in remote myocardium, MFRs in viable regions were similar (1.39 ± 0.56 vs 1.70 ± 0.45, p > 0.05) but were significantly lower in nonviable regions (1.23 ± 0.43, p < 0.001). Moreover, the FDG and thus glucose extraction was higher in viable than in remote (1.40 ± 0.14 vs 0.90 ± 0.20, p < 0.001) and in nonviable regions (1.13 ± 0.21, p < 0.001). The extraction of FDG in viable regions was independent of rest MBF but correlated inversely with MFRs (r =-0.424, p < 0.05). No correlation between the FDG extraction and MFR was observed in nonviable regions., Conclusion: As in the animal model, decreasing MFRs in viable myocardium are associated with increasing glucose extraction that likely reflects a metabolic adaptation of remodeling hibernating myocytes., Competing Interests: None.

The axial field of view (AFOV) of the current generation of clinical whole-body PET scanners range from 15-22 cm, which limits sensitivity and renders applications such as whole-body dynamic imaging or imaging of very low activities in whole-body cellular tracking studies, almost impossible. Generally, extending the AFOV significantly increases the sensitivity and count-rate performance. However, extending the AFOV while maintaining detector thickness has significant cost implications. In addition, random coincidences, detector dead time, and object attenuation may reduce scanner performance as the AFOV increases. In this paper, we use Monte Carlo simulations to find the optimal scanner geometry (i.e. AFOV, detector thickness and acceptance angle) based on count-rate performance for a range of scintillator volumes ranging from 10 to 93 l with detector thickness varying from 5 to 20 mm. We compare the results to the performance of a scanner based on the current Siemens Biograph mCT geometry and electronics. Our simulation models were developed based on individual components of the Siemens Biograph mCT and were validated against experimental data using the NEMA NU-2 2007 count-rate protocol. In the study, noise-equivalent count rate (NECR) was computed as a function of maximum ring difference (i.e. acceptance angle) and activity concentration using a 27 cm diameter, 200 cm uniformly filled cylindrical phantom for each scanner configuration. To reduce the effect of random coincidences, we implemented a variable coincidence time window based on the length of the lines of response, which increased NECR performance up to 10% compared to using a static coincidence time window for scanners with a large maximum ring difference values. For a given scintillator volume, the optimal configuration results in modest count-rate performance gains of up to 16% compared to the shortest AFOV scanner with the thickest detectors. However, the longest AFOV of approximately 2 m with 20 mm thick detectors resulted in performance gains of 25-31 times higher NECR relative to the current Siemens Biograph mCT scanner configuration.

Unlabelled: Logan graphical analysis with cerebellum as reference region has been widely used for the estimation of the distribution volume ratio (DVR) of [(18)F]FDDNP as a measure of amyloid burden and tau deposition in human brain because of its simplicity and computational ease. However, spurious parametric DVR images may be produced with shorter scanning times and when the noise level is high. In this work, we have characterized a relative-equilibrium-based (RE) graphical method against the Logan analysis for parametric imaging and region-of-interest (ROI) analysis., Methods: Dynamic [(18)F]FDDNP PET scans were performed on 9 control subjects and 12 patients diagnosed with Alzheimer's disease. Using the cerebellum as reference input, regional DVR estimates were derived using both the Logan analysis and the RE plot approach. Effects on DVR estimates obtained at voxel and ROI levels by both graphical approaches using data in different time windows were investigated and compared with the standard values derived using the Logan analysis on a voxel-by-voxel basis for the time window of 35-125 min used in previous studies., Results: Larger bias and variability were observed for DVR estimates obtained by the Logan graphical analysis at the voxel level when short time windows (85-125 and 45-65 min) were used, because of high noise levels in voxel-wise parametric imaging. However, when the Logan graphical analysis was applied at the ROI level over those short time windows, the DVR estimates did not differ significantly from the standard values derived using the Logan analysis on the voxel level for the time window of 35-125 min, and their bias and variability were remarkably lower. Conversely, the RE plot approach was more robust in providing DVR estimates with less bias and variability even when short time windows were used. The DVR estimates obtained at voxel and ROI levels were consistent. No significant differences were observed in DVR estimates obtained by the RE plot approach for all paired comparisons with the standard values., Conclusions: The RE plot approach provides less noisy parametric images and gives consistent and reliable regional DVR estimates at both voxel and ROI levels, indicating that it is preferred over the Logan graphical analysis for analyzing [(18)F]FDDNP PET data., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Unlabelled: With the dismal prognosis for malignant glioma patients, survival predictions become key elements in patient management. This study compares the value of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and MRI for early outcome predictions in patients with recurrent malignant glioma on bevacizumab therapy., Methods: Thirty patients treated with bevacizumab combination therapy underwent (18)F-FLT PET immediately before and at 2 and 6 wk after the start of treatment. A metabolic treatment response was defined as a decrease of equal to or greater than 25% in tumor (18)F-FLT uptake (standardized uptake values) from baseline using receiver-operating-characteristic analysis. MRI treatment response was assessed at 6 wk according to the Response Assessment in Neurooncology criteria. (18)F-FLT responses at different times were compared with MRI response and correlated with progression-free survival and overall survival using Kaplan-Meier analysis. Metabolic response based on (18)F-FLT was further compared with other outcome predictors using Cox regression analysis., Results: Early and late changes in tumor (18)F-FLT uptake were more predictive of overall survival than MRI criteria (P < 0.001 and P = 0.01, respectively). (18)F-FLT uptake changes were also predictive of progression-free survival (P < 0.001). The median overall survival for responders was 3.3 times longer than for nonresponders based on (18)F-FLT PET criteria (12.5 vs. 3.8 mo, P < 0.001) but only 1.4 times longer using MRI assessment (12.9 vs. 9.0 mo, P = 0.05). On the basis of the 6-wk (18)F-FLT PET response, there were 16 responders (53%) and 14 nonresponders (47%), whereas MRI identified 9 responders (7 partial response, 2 complete response, 31%) and 20 nonresponders (13 stable disease, 7 progressive disease, 69%). In 7 of the 8 discrepant cases between MRI and PET, (18)F-FLT PET was able to demonstrate response earlier than MRI. Among various outcome predictors, multivariate analysis identified (18)F-FLT PET changes at 6 wk as the strongest independent survival predictor (P < 0.001; hazard ratio, 10.051)., Conclusion: Changes in tumor (18)F-FLT uptake were highly predictive of progression-free and overall survival in patients with recurrent malignant glioma on bevacizumab therapy. (18)F-FLT PET seems to be more predictive than MRI for early treatment response.

Purpose: The primary objective of this study was to investigate whether changes in 3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT) kinetic parameters, taken early after the start of therapy, could predict overall survival (OS) and progression-free survival (PFS) in patients with recurrent malignant glioma undergoing treatment with bevacizumab and irinotecan., Experimental Design: High-grade recurrent brain tumors were investigated in 18 patients (8 male and 10 female), ages 26 to 76 years. Each had 3 dynamic positron emission tomography (PET) studies as follows: at baseline and after 2 and 6 weeks from the start of treatment, ¹⁸F-FLT (2.0 MBq/kg) was injected intravenously, and dynamic PET images were acquired for 1 hour. Factor analysis generated factor images from which blood and tumor uptake curves were derived. A three-compartment, two-tissue model was applied to estimate tumor ¹⁸F-FLT kinetic rate constants using a metabolite- and partial volume-corrected input function. Different combinations of predictor variables were exhaustively searched in a discriminant function to accurately classify patients into their known OS and PFS groups. A leave-one-out cross-validation technique was used to assess the generalizability of the model predictions., Results: In this study population, changes in single parameters such as standardized uptake value or influx rate constant did not accurately classify patients into their respective OS groups (<1 and ≥ 1 year; hit ratios ≤ 78%). However, changes in a set of ¹⁸F-FLT kinetic parameters could perfectly separate these two groups of patients (hit ratio = 100%) and were also able to correctly classify patients into their respective PFS groups (<100 and ≥ 100 days; hit ratio = 88%)., Conclusions: Discriminant analysis using changes in ¹⁸F-FLT kinetic parameters early during treatment seems to be a powerful method for evaluating the efficacy of therapeutic regimens., (©2011 AACR.)

Unlabelled: (18)F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, biodistribution, human safety, tolerability, and early elimination of (18)F activity in urine after injection of a single dose of the tracer at rest in healthy subjects., Methods: Thirteen healthy subjects were injected with 170-244 MBq (4.6-6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software., Results: The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64-12.41 percentage injected dose)., Conclusion: These preliminary data suggest that (18)F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.

Deviations in reward sensitivity and behavioral flexibility, particularly in the ability to change or stop behaviors in response to changing environmental contingencies, are important phenotypic dimensions of several neuropsychiatric disorders. Neuroimaging evidence suggests that variation in dopamine signaling through dopamine D(2)-like receptors may influence these phenotypes, as well as associated psychiatric conditions, but the specific neurocognitive mechanisms through which this influence is exerted are unknown. To address this question, we examined the relationship between behavioral sensitivity to reinforcement during discrimination learning and D(2)-like receptor availability in vervet monkeys. Monkeys were assessed for their ability to acquire, retain, and reverse three-choice, visual-discrimination problems, and once behavioral performance had stabilized, they received positron emission tomography (PET) scans. D(2)-like receptor availability in dorsal aspects of the striatum was not related to individual differences in the ability to acquire or retain visual discriminations but did relate to the number of trials required to reach criterion in the reversal phase of the task. D(2)-like receptor availability was also strongly correlated with behavioral sensitivity to positive, but not negative, feedback during learning. These results go beyond electrophysiological findings by demonstrating the involvement of a striatal dopaminergic marker in individual differences in feedback sensitivity and behavioral flexibility, providing insight into the neural mechanisms that are affected in neuropsychiatric disorders that feature these deficits.

Unlabelled: 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is used as a biomarker of cell proliferation. We investigated the kinetics of (18)F-FLT during treatment of malignant glioma with bevacizumab and irinotecan., Methods: Fifteen patients with recurrent high-grade brain tumors (2 grade III, 13 grade IV) were studied at baseline (study 1 [S1]), after 1 course of therapy (2 wk, study 2 [S2]), and at the end of therapy (6 wk, study 3 [S3]). (18)F-FLT (1.5 MBq/kg) was administered intravenously, and dynamic PET was performed for 1 h. Curves representing blood clearance and tumor uptake were derived from factor images and summed frames with thresholding techniques or with a fixed cube. The standard (18)F-FLT model was used to estimate the rate constants. (18)F-FLT uptake was measured at 2 time points (early standardized uptake value [SUV(early)] and late SUV [SUV(late)])., Results: Parameters appeared similar for curves derived from factor images and summed frames; the steepest drop occurred between S1 and S2 for transport, influx, SUV(early), and SUV(late). Three groups were distinguished on the basis of clinical outcome: patients who died within 6 mo (group 1 [G1], n = 4), survived 6-12 mo (group 2 [G2], n = 6), and survived more than 1 y (group 3 [G3], n = 5). None of the rate constants was significantly different between the groups. Long-term survivors (G3) showed a significantly different SUV change (in percentage) between S1 and S3, whereas short-term survivors (G1 and G2) did not., Conclusion: Overall, the relative SUV change from S1 to S3 predicted a favorable clinical outcome, whereas the SUV change from S1 to S2 did not. Long-term survivors (G3) showed a significant drop in SUV from S1 to S2 and from S1 to S3. Significant correlations were found between SUV and both the rate constant and the influx rate. The correlation coefficient between SUV(late) and influx rate was 0.91, permitting response monitoring by the measurement of (18)F-FLT uptake changes.

Purpose: Subcortical white matter is known to be relatively unaffected by amyloid deposition in Alzheimer's disease (AD). We investigated the use of subcortical white matter as a reference region to quantify [(18)F]FDDNP binding in the human brain., Methods: Dynamic [(18)F]FDDNP PET studies were performed on 7 control subjects and 12 AD patients. Population efflux rate constants (k(')(2)) from subcortical white matter (centrum semiovale) and cerebellar cortex were derived by a simplified reference tissue modeling approach incorporating physiological constraints. Regional distribution volume ratio (DVR) estimates were derived using Logan and simplified reference tissue approaches, with either subcortical white matter or cerebellum as reference input. Discriminant analysis with cross-validation was performed to classify control subjects and AD patients., Results: The population estimates of k(')(2) in subcortical white matter did not differ significantly between control subjects and AD patients but the variability of individual estimates of k(')(2) determined in white matter was lower than that in cerebellum. Logan DVR showed dependence on the efflux rate constant in white matter. The DVR estimates in the frontal, parietal, posterior cingulate, and temporal cortices were significantly higher in the AD group (p<0.01). Incorporating all these regional DVR estimates as predictor variables in discriminant analysis yielded accurate classification of control subjects and AD patients with high sensitivity and specificity, and the results agreed well with those using the cerebellum as the reference region., Conclusion: Subcortical white matter can be used as a reference region for quantitative analysis of [(18)F]FDDNP with the Logan method which allows more accurate and less biased binding estimates, but a population efflux rate constant has to be determined a priori.

Unlabelled: Head movement during a PET scan (especially a dynamic scan) can affect both the qualitative and the quantitative aspects of an image, making it difficult to accurately interpret the results. The primary objective of this study was to develop a retrospective image-based movement correction (MC) method and evaluate its implementation on dynamic 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ((18)F-FDDNP) PET images of cognitively intact controls and patients with Alzheimer's disease (AD)., Methods: Dynamic (18)F-FDDNP PET images, used for in vivo imaging of beta-amyloid plaques and neurofibrillary tangles, were obtained from 12 AD patients and 9 age-matched controls. For each study, a transmission scan was first acquired for attenuation correction. An accurate retrospective MC method that corrected for transmission-emission and emission-emission misalignments was applied to all studies. No restriction was assumed for zero movement between the transmission scan and the first emission scan. Logan analysis, with the cerebellum as the reference region, was used to estimate various regional distribution volume ratio (DVR) values in the brain before and after MC. Discriminant analysis was used to build a predictive model for group membership, using data with and without MC., Results: MC improved the image quality and quantitative values in (18)F-FDDNP PET images. In this subject population, no significant difference in DVR value was observed in the medial temporal (MTL) region of controls and patients with AD before MC. However, after MC, significant differences in DVR values in the frontal, parietal, posterior cingulate, MTL, lateral temporal (LTL), and global regions were seen between the 2 groups (P < 0.05). In controls and patients with AD, the variability of regional DVR values (as measured by the coefficient of variation) decreased on average by more than 18% after MC. Mean DVR separation between controls and patients with AD was higher in frontal, MTL, LTL, and global regions after MC. Group classification by discriminant analysis based on (18)F-FDDNP DVR values was markedly improved after MC., Conclusion: The streamlined and easy-to-use MC method presented in this work significantly improves the image quality and the measured tracer kinetics of (18)F-FDDNP PET images. The proposed MC method has the potential to be applied to PET studies on patients having other disorders (e.g., Down syndrome and Parkinson's disease) and to brain PET scans with other molecular imaging probes.