Description: There is significant interest in a better understanding of the genetic underpinnings of the increased glucose metabolic rates of cancer cells. Thyroid cancer demonstrates a broad variability of 18 F-FDG uptake as well as several well-characterized oncogenic mutations. In this study, we evaluated the differences in glucose metabolism of the BRAF V600E mutation versus BRAF wild-type ( BRAF -WT) in patients with metastatic differentiated thyroid cancer (DTC) and poorly differentiated thyroid cancer (PDTC). Methods: Forty-eight DTC and 34 PDTC patients who underwent 18 F-FDG PET/CT for tumor staging were identified from a database search. All patients were tested for the BRAF V600E mutation and assigned to 1 of 2 groups: BRAF V600E mutated and BRAF -WT. 18 F-FDG uptake of tumor tissue was quantified by maximum standardized uptake value (SUV max ) of the hottest malignant lesion in 6 prespecified body regions (thyroid bed, lymph nodes, lung, bone, soft tissue, and other). When there were multiple lesions in 1 of the prespecified body regions, only the 1 with the highest 18 F-FDG uptake was analyzed. Results: In the DTC cohort, 24 tumors harbored a BRAF V600E mutation, whereas 24 tumors were BRAF -WT. 18 F-FDG uptake of BRAF V600E -positive lesions (median SUV max , 6.3; n = 53) was significantly higher than that of BRAF -WT lesions ( n = 39; median SUV max , 4.7; P = 0.019). In the PDTC group, only 5 tumors were BRAF V600E -positive, and their 18 F-FDG uptake was not significantly different from the BRAF -WT tumors. There was also no significant difference between the SUV max of all DTCs and PDTCs, regardless of BRAF mutational status ( P = 0.90). Conclusion: These data suggest that BRAF V600E -mutated DTCs are significantly more 18 F-FDG–avid than BRAF -WT tumors. The effect of BRAF V600E on tumor glucose metabolism in PDTC needs further study in larger groups of patients.

Description: 90 Y has been used to label various new therapeutic radiopharmaceuticals. However, measuring the radiation dose delivered by 90 Y is challenging because of the absence of suitable emissions and its low abundance of positron emissions. For the treatment of prostate cancer, radiolabeled gastrin-releasing peptide receptor (GRPr) antagonists have yielded promising results in mouse models. In this study, we evaluated whether Cerenkov luminescence imaging (CLI) could be used to determine radiation doses of a 90 Y-labeled GRPr antagonist in nude mice. Methods: Mice bearing subcutaneous prostate cancer xenografts were injected with 0.74–18.5 MBq of the 90 Y-labeled GRPr antagonist DOTA-AR and underwent in vivo and ex vivo CLI at 1–48 h after injection. After imaging, animals were sacrificed, their tumors and organs were harvested, and the activity concentration was measured by liquid scintillation counting. In a second set of experiments, Cerenkov photon counts for tumor and kidney on in vivo CLI were converted to activity concentrations using conversion factors determined from the first set of experiments. Results: 90 Y-DOTA-AR concentration in the 3 tumor models ranged from 0.5% to 4.8% of the injected activity per gram at 1 h after injection and decreased to 0.05%–0.15 injected activity per gram by 48 h after injection. A positive correlation was found between tumor activity concentrations and in vivo CLI signal ( r 2 = 0.94). A similar correlation was found for the renal activity concentration and in vivo Cerenkov luminescence ( r 2 = 0.98). Other organs were not distinctly visualized on the in vivo images, but ex vivo CLI was also correlated with the radioactivity concentration ( r 2 = 0.35–0.94). Using the time–activity curves from the second experiment, we calculated radiation doses to tumor and kidney of 0.33 ± 0.12 (range, 0.21–0.66) and 0.06 ± 0.01 (range, 0.05–0.08) Gy/MBq, respectively. Conclusion: CLI is a promising, low-cost modality to measure individual radiation doses of 90 Y-labeled compounds noninvasively. The use of Cerenkov imaging is expected to facilitate the development and comparison of 90 Y-labeled compounds for targeted radiotherapy.

Description: Early prognostic stratification is desirable in patients with suspected atypical parkinsonian syndromes (APSs) for optimal treatment and counseling. We investigated the prognostic value of imaging disease-specific metabolism patterns with 18 F-FDG PET compared with that of clinical diagnosis. Methods: Seventy-eight patients with suspected APS at study inclusion underwent a follow-up of up to 5.9 y after prospective 18 F-FDG PET imaging. Survival data were analyzed by Kaplan–Meier and Cox regression analyses according to diagnostic classifications provided by 18 F-FDG PET at baseline and clinical diagnoses after a median follow-up of 1 y after PET. Results: Forty-four of 78 patients were alive 4.7 ± 0.6 y after PET. Patients diagnosed with an APS by PET or 1-y clinical follow-up showed a significantly shorter median survival time (4.1 y, age-adjusted hazard ratios [HRs] = 3.8 for both classifiers) than those diagnosed with Lewy-body diseases (LBDs; majority Parkinson disease [PD]; median survival time not reached). Subgroup classifications of progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) or multiple-system atrophy (MSA) by PET and clinical follow-up were associated with significantly shorter survival than PD. Age-adjusted mortality was significantly increased for PSP/CBD (HR = 5.2) and MSA (HR = 5.6) classified by PET, but for PSP/CBD only when diagnosed by clinical follow-up (HR = 4.5). Patients with a PET pattern suggestive of PD with dementia/dementia with Lewy bodies (PDD/DLB) exhibited a trend toward shorter survival than those with PD ( P = 0.07), whereas patients classified as PDD/DLB by clinical follow-up did not ( P = 0.65). Conclusion: 18 F-FDG PET is an early predictor of survival in patients with clinically suspected APS. Detection of cortical or subcortical hypometabolism by 18 F-FDG PET is an unfavorable predictor. Risk stratification by 18 F-FDG PET appears to be at least as predictive as the 1-y follow-up clinical diagnosis. This finding strongly supports the early inclusion of PET imaging in patient care.

Description: PET/CT with the glucose analog 18 F-FDG has several potential applications for monitoring tumor response to therapy in patients with non–small cell lung cancer (NSCLC). A prerequisite for many of these applications is detailed knowledge of the repeatability of quantitative parameters derived from 18 F-FDG PET/CT studies. Methods: The repeatability of the 18 F-FDG signal was evaluated in 2 prospective multicenter trials. Patients with advanced NSCLC (tumor stage III–IV) underwent two 18 F-FDG PET/CT studies while not receiving therapy. Tumor 18 F-FDG uptake was quantified by measurement of the maximum standardized uptake value within a lesion (SUV max ) and the average SUV within a small volume of interest around the site of maximum uptake (SUV peak ). Analysis was performed for the lesion in the chest with the highest 18 F-FDG uptake and a size of at least 2 cm (target lesion) as well as for up to 6 additional lesions per patient. Repeatability was assessed by Bland–Altman plots and calculation of 95% repeatability coefficients (RCs) of the log-transformed SUV differences. Results: Test–retest repeatability was assessed in 74 patients (34 from the ACRIN 6678 trial and 40 from the Merck MK-0646-008 trial). SUV peak was 11.57 ± 7.89 g/mL for the ACRIN trial and 6.89 ± 3.02 for the Merck trial. The lower and upper RCs were –28% (95% confidence interval [CI], –35% to –23%) and +39% (95% CI, 31% to 54%) in the ACRIN trial, indicating that a decrease of SUV peak by more than 28% or an increase by more than 39% has a probability of less than 2.5%. The corresponding RCs from the Merck trial were –35% (95% CI, –42% to –29%) and +53% (95% CI, 41% to 72%). Repeatability was similar for SUV max of the target lesion, averaged SUV max , and averaged SUV peak of up to 6 lesions per patient. Conclusion: The variability of repeated measurements of tumor 18 F-FDG uptake in patients with NSCLC is somewhat larger than previously reported in smaller single-center studies but comparable to that of gastrointestinal malignancies in a previous multicenter trial. The variability of measurements supports the definitions of tumor response according to PET Response Criteria in Solid Tumors.

Description: This paper presents our adaptation of Fryback and Thornbury’s hierarchical scheme for modeling the efficacy of diagnostic imaging systems. The original scheme was designed to evaluate new medical imaging systems but is less successful when applied to evaluate new radiopharmaceuticals. The proposed adaptation, which is specifically directed toward evaluating targeted imaging agents, has 6 levels: in vitro characterization, in vivo animal studies, initial human studies, impact on clinical care (change in management), impact on patient outcome, and societal efficacy. These levels, particularly the first four, implicitly define the sequence of studies needed to move an agent from the radiochemistry synthesis laboratory to the clinic. Completion of level 4 (impact on clinical care) should be sufficient for initial approval and reimbursement. We hope that the adapted scheme will help streamline the process and assist in bringing new targeted radiopharmaceuticals to approval over the next few years.

Description: The aim of this study was to investigate the value of pharmacokinetic modeling for quantifying 11 C-choline uptake in patients with recurrent prostate cancer. Methods: In total, 194 patients with clinically suspected recurrence of prostate cancer underwent 11 C-choline dynamic PET over the pelvic region (0–8 min), followed by a 6-min static acquisition at about 25 min after injection. Regions of interest were drawn over sites of disease identified by a radiologist with experience in nuclear medicine. 11 C-choline uptake and pharmacokinetics were evaluated by SUV, graphical analysis (Patlak plot; K i P ), and 1- and 2-compartment pharmacokinetic models ( K 1 , K 1 / k 2 , k 3 , k 4 , and the macro parameter K i C ). Twenty-four local recurrences, 65 metastatic lymph nodes, 19 osseous metastases, and 60 inflammatory lymph nodes were included in the analysis, which was subsequently repeated for regions of interest placed over the gluteus maximus muscle and adipose tissue as a control. Results: SUV mean and K i P were 3.60 ± 2.16 and 0.28 ± 0.22 min –1 in lesions, compared with 2.11 ± 1.33 and 0.15 ± 0.10 min –1 in muscle and 0.26 ± 0.07 and 0.02 ± 0.01 min –1 in adipose tissue. According to the Akaike information criterion, the 2-compartment irreversible model was most appropriate in 85% of lesions and resulted in a K 1 of 0.79 ± 0.98 min –1 (range, 0.11–7.17 min –1 ), a K 1 / k 2 of 2.92 ± 3.52 (range, 0.31–20.00), a k 3 of 0.36 ± 0.30 min –1 (range, 0.00–1.00 min –1 ) and a K i C of 0.28 ± 0.22 min –1 (range, 0.00–1.33 min –1 ). The Spearman between SUV and K i P , between SUV and K i C , and between K i P and K i C was 0.94, 0.91, and 0.97, respectively, and that between SUV and K 1 , between SUV and K 1 / k 2 , and between SUV and k 3 was 0.70, 0.44, and 0.33, respectively. Malignant lymph nodes exhibited a higher SUV, K i P , and K i C than benign lymph nodes. Conclusion: Although 11 C-choline pharmacokinetic modeling has potential to uncouple the contributions of different processes leading to intracellular entrapment of 11 C-choline, the high correlation between SUV and both K i P and K i C supports the use of simpler SUV methods to evaluate changes in 11 C-choline uptake and metabolism for treatment monitoring.

Description: 18 F-fluorodihydrotestosterone ( 18 F-FDHT) is a radiolabeled analog of the androgen receptor’s primary ligand that is currently being credentialed as a biomarker for prognosis, response, and pharmacodynamic effects of new therapeutics. As part of the biomarker qualification process, we prospectively assessed its reproducibility and repeatability in men with metastatic castration-resistant prostate cancer. Methods: We conducted a prospective multiinstitutional study of metastatic castration-resistant prostate cancer patients undergoing 2 (test/retest) 18 F-FDHT PET/CT scans on 2 consecutive days. Two independent readers evaluated all examinations and recorded SUVs, androgen receptor–positive tumor volumes, and total lesion uptake for the most avid lesion detected in each of 32 predefined anatomic regions. The relative absolute difference and reproducibility coefficient (RC) of each metric were calculated between the test and retest scans. Linear regression analyses, intraclass correlation coefficients (ICCs), and Bland–Altman plots were used to evaluate repeatability of 18 F-FDHT metrics. The coefficient of variation and ICC were used to assess interobserver reproducibility. Results: Twenty-seven patients with 140 18 F-FDHT–avid regions were included. The best repeatability among 18 F-FDHT uptake metrics was found for SUV metrics (SUV max, SUV mean , and SUV peak ), with no significant differences in repeatability among them. Correlations between the test and retest scans were strong for all SUV metrics ( R 2 ≥ 0.92; ICC ≥ 0.97). The RCs of the SUV metrics ranged from 21.3% (SUV peak ) to 24.6% (SUV max ). The test and retest androgen receptor–positive tumor volumes and TLU, respectively, were highly correlated ( R 2 and ICC ≥ 0.97), although variability was significantly higher than that for SUV (RCs 〉 46.4%). The prostate-specific antigen levels, Gleason score, weight, and age did not affect repeatability, nor did total injected activity, uptake measurement time, or differences in uptake time between the 2 scans. Including the most avid lesion per patient, the 5 most avid lesions per patient, only lesions 4.2 mL or more, only lesions with an SUV of 4 g/mL or more, or normalizing of SUV to area under the parent plasma activity concentration–time curve did not significantly affect repeatability. All metrics showed high interobserver reproducibility (ICC 〉 0.98; coefficient of variation 〈 0.2%–10.8%). Conclusion: Uptake metrics derived from 18 F-FDHT PET/CT show high repeatability and interobserver reproducibility.

Description: 123 I-meta-iodobenzylguanidine ( 123 I-MIBG) imaging is currently a mainstay in the evaluation of many neuroendocrine tumors, especially neuroblastoma. 123 I-MIBG imaging has several limitations that can be overcome by the use of a PET agent. 18 F-meta-fluorobenzylguanidine ( 18 F-MFBG) is a PET analog of MIBG that may allow for single-day, high-resolution quantitative imaging. We conducted a first-in-human study of 18 F-MFBG PET imaging to evaluate the safety, feasibility, pharmacokinetics, and dosimetry of 18 F-MFBG in neuroendocrine tumors (NETs). Methods: Ten patients (5 with neuroblastoma and 5 with paraganglioma/pheochromocytoma) received 148–444 MBq (4–12mCi) of 18 F-MFBG intravenously followed by serial whole-body imaging at 0.5–1, 1–2, and 3–4 after injection. Serial blood samples (a total of 6) were also obtained starting at 5 min after injection to as late as 4 h after injection; whole-body distribution and blood clearance data, lesion uptake, and normal-tissue uptake were determined, and radiation-absorbed doses to normal organs were calculated using OLINDA. Results: No side effects were seen in any patient after 18 F-MFBG injection. Tracer distribution showed prominent activity in the blood pool, liver, and salivary glands that decreased with time. Mild uptake was seen in the kidneys and spleen, which also decreased with time. Urinary excretion was prominent, with an average of 45% of the administered activity in the bladder by 1 h after injection; whole-body clearance was monoexponential, with a mean biologic half-life of 1.95 h, whereas blood clearance was biexponential, with a mean biologic half-life of 0.3 h (58%) for the rapid α phase and 6.1 h (42%) for the slower β phase. The urinary bladder received the highest radiation dose with a mean absorbed dose of 0.186 ± 0.195 mGy/MBq. The mean total-body dose was 0.011 ± 0.011 mGy/MBq, and the effective dose was 0.023 ± 0.012 mSv/MBq. Both skeletal and soft-tissue lesions were visualized with high contrast. The SUVmax (mean ± SD ) of lesions at 1–2 h after injection was 8.6 ± 9.6. Conclusion: Preliminary data show that 18 F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. PET imaging with 18 F-MFBG allows for same-day imaging of NETs. 18 F-MFBG appears highly promising for imaging of patients with NETs, especially children with neuroblastoma.

Description: Prostate-specific membrane antigen (PSMA)–ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data.