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Our aims were (1) by computed tomography (CT) to establish a population database for pancreas volume (parenchyma and fat) from birth to age 100 years, (2) in adults, to establish the impact of gender, obesity, and the presence or absence of type-2 diabetes on pancreatic volume (parenchyma and fat), and (3) to confirm the latter histologically from pancreatic tissue obtained at autopsy with a particular emphasis on whether pancreatic fat is increased in type-2 diabetes. We measured pancreas volume in 135 children and 1,886 adults (1,721 nondiabetic and 165 with type-2 diabetes) with no history of pancreas disease who had undergone abdominal CT scan between 2003 and 2006. Pancreas volume was computed from the contour of the pancreas on each CT image. In addition to total pancreas volume, parenchymal volume, fat volume, and fat/parenchyma ratio (F/P ratio) were determined by CT density. We also quantified pancreatic fat in autopsy tissue of 47 adults (24 nondiabetic and 23 with type-2 diabetes). During childhood and adolescence, the volumes of total pancreas, pancreatic parenchyma, and fat increase linearly with age. From age 20-60 years, pancreas volume reaches a plateau (72.4 +/- 25.8 cm(3) total; 44.5 +/- 16.5 cm(3) parenchyma) and then declines thereafter. In adults, total ( approximately 32%), parenchymal ( approximately 13%), and fat ( approximately 68%) volumes increase with obesity. Pancreatic fat content also increases with aging but is not further increased in type-2 diabetes. We provide lifelong population data for total pancreatic, parenchymal, and fat volumes in humans. Although pancreatic fat increases with aging and obesity, it is not increased in type-2 diabetes.

The phase 3 VISION trial demonstrated that [ 177 Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]-positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [ 177 Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [ 177 Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [ 177 Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [ 177 Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Fibroblast activation protein (FAP)-inhibitor (FAPI)-PET tracers allow imaging of the FAP-expressing cancer associated fibroblasts (CAF) and also the normal activated fibroblasts (NAF) involved in inflammation/fibrosis that may be present after invasive medical interventions. We evaluated [68Ga]Ga-FAPI-46 uptake patterns post-medical/invasive non-systemic interventions., Methods: This single-center retrospective analysis was conducted in 79 consecutive patients who underwent [ 68 Ga]Ga-FAPI-46 PET/CT. Investigators reviewed prior patient medical/invasive interventions (surgery, endoscopy, biopsy, radiotherapy, foreign body placement (FBP) defined as implanted medical/surgical material present at time of scan) and characterized the anatomically corresponding FAPI uptake intensity both visually (positive if above surrounding background) and quantitatively (SUVmax). Interventions with missing data/images or confounders of [ 68 Ga]Ga-FAPI-46 uptake (partial volume effect, other cause of increased uptake) were excluded. Available correlative FDG, DOTATATE and PSMA PET/CTs were analyzed when available., Results: 163 medical/invasive interventions (mostly surgeries (49%), endoscopies (18%) and non-surgical biopsies (10%)) in 60 subjects were included for analysis. 43/163 (26%) involved FBP. FAPI uptake occurred in 24/163 (15%) of interventions (average SUVmax 3.2 (mild), range 1.5-5.1). The median time-interval post-intervention to FAPI-PET was 47.5 months and was shorter when FAPI uptake was present (median 9.5 months) than when absent (median 60.1 months; p = 0.001). Cut-off time beyond which no FAPI uptake would be present post-intervention without FBP was 8.2 months, with a sensitivity, specificity, positive predictive value and negative predictive value of 82, 90, 99 and 31% respectively. No optimal cutoff point could be determined when considering interventions with FBP. No significant difference was detected between frequency of [ 68 Ga]Ga-FAPI-46 and [ 18 F]FDG uptake in intervention sites. Compared to [ 68 Ga]Ga-PSMA-11, [ 68 Ga]Ga-FAPI-46 revealed more frequent and intense post-interventional tracer uptake., Conclusion: [ 68 Ga]Ga-FAPI-46 uptake from medical/invasive interventions without FBP appears to be time dependent, nearly always absent beyond 8 months post-intervention, but frequently present for years with FBP., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Somatostatin receptors (SSTR) represent an ideal target for nuclear theranostics applications in neuroendocrine tumors (NET). Studies suggest that high uptake on SSTR-PET is associated with response to SSTR peptide receptor radionuclide therapy (PRRT). The purpose of this study was to evaluate the role of baseline whole-body (WB) 68  Ga-DOTATATE PET/CT (SSTR-PET) quantitative parameters, and the presence of NET lesions without uptake on SSTR-PET, as outcome prognosticator in patients with NET treated with PRRT., Methods: Patients with NET who underwent at least 4 177 Lu-DOTATATE PRRT cycles between 07/2016 and 03/2021 were included in this retrospective analysis if they fulfilled the following inclusion criteria: SSTR-PET within 6 months of 1st PRRT cycle, follow-up CT and/or MRI performed > 6 months after the 4th cycle of PRRT. The SSTR-PET analysis consisted of a visual and a quantitative analysis done independently by two board-certified physicians. The visual analysis assessed the presence of NET lesions visible on the SSTR-PET co-registered CT. The quantitative analysis consisted in contouring all SSTR-avid lesions on SSTR-PET and extracting WB quantitative parameters: SUVmean (WB-SUVmean), SUVmax of the lesion with highest uptake (H-SUVmax), and tumor volume (WB-TV). WB-SSTR-PET parameters and the presence of SSTR-PET-negative lesions were correlated to radiologic response (assessed by RECIST 1.1 criteria) and progression-free survival (PFS). Fisher's exact test, Mann-Whitney's U test and Kaplan-Meier curves with Cox-regression analysis were used for the statistical analysis., Results: Forty patients (F/M: 21/19; 34/40 with gastro-entero-pancreatic (GEP) NET, 6/40 with non-GEP NET) were included in the analysis. The median follow-up period after the 4th PRRT cycle was 25.7 months (range 15.2-59.1). Fourteen/40 (35%) patients showed radiologic response (RECIST PR). PFS event was observed in 17/40 (42.5%) patients. Thirteen/40 (32.5%) patients had SSTR-PET-negative lesions at baseline. Higher WB-SUVmean and H-SUVmax were associated with better response (p = 0.015 and 0.005, respectively). The presence of SSTR-PET-negative lesions and lower WB-SUVmean were associated with shorter PFS (p = 0.026 and 0.008, respectively)., Conclusion: Visual and quantitative analyses of baseline SSTR-PET can yield valuable information to prognosticate outcomes after 177 Lu-DOTATATE PRRT., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

177 Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy effectively treats metastatic castration-resistant prostate cancer. Patients requiring treatment, and consequently the number of theranostic centers, are expected to increase significantly after Food and Drug Administration and European Medicines Agency approval. This requires standardization or harmonization among theranostic centers. The aim of this study was to assess operational differences and similarities among 177 Lu-PSMA treatment centers. Methods: A questionnaire comprising 62 items, designed by a core team of 5 physicians and externally reviewed by international experts, was developed. Study participants were asked to provide answers about their center, patient selection, radiopharmaceuticals, clinical assessment before and after 177 Lu-PSMA treatments, laboratory values, treatment discontinuation, posttreatment imaging, and general information. An invitation e-mail to participate in the study was sent in June 2022. Duplicates were removed to allow for only one valid response per center. Results: Ninety-five of 211 (45%) contacted centers completed the questionnaire. Most participating centers were in Europe (51%), followed by America (22%) and Asia (22%). During the 12 mo before this study, a total of 5,906 patients received 177 Lu-PSMA therapy at the 95 participating centers. Most of these patients were treated in Europe (2,840/5,906; 48%), followed by Asia (1,313/5,906; 22%) and Oceania (1,225/5,906; 21%). PSMA PET eligibility for 177 Lu-PSMA was determined most frequently using 68 Ga-PSMA-11 (77%). Additional pretherapy imaging included 18 F-FDG PET/CT, CT, renal scintigraphy, and bone scintigraphy at 41 (49%), 27 (32%), 25 (30%), and 13 (15%), respectively, of the 84 centers for clinical standard of care, compassionate care, or local research protocols and 11 (26%), 25 (60%), 9 (21%), and 28 (67%), respectively, of the 42 centers for industry-sponsored trials. PSMA PET eligibility criteria included subjective qualitative assessment of PSMA positivity at 33% of centers, VISION criteria at 23%, and TheraP criteria at 13%. The mean standard injected activity per cycle was 7.3 GBq (range, 5.5-11.1 GBq). Sixty-two (65%) centers applied standardized response assessment criteria, and PSMA PET Progression Criteria were the most applied (37%). Conclusion: Results from this international survey revealed interinstitutional differences in several aspects of 177 Lu-PSMA radionuclide therapy, including patient selection, administered activity, and the response assessment strategy. Standardization or harmonization of protocols and dedicated training are desirable in anticipation of increasing numbers of patients and theranostic centers., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Prostate-specific membrane antigen (PSMA) PET has a higher accuracy than CT and bone scans to stage patients with prostate cancer. We do not understand how to apply clinical trial data based on conventional imaging to patients staged using PSMA PET. Therefore, we aimed to evaluate the ability of bone scans to detect osseous metastases using PSMA PET as a reference standard. Methods: In this multicenter retrospective diagnostic study, 167 patients with prostate cancer, who were imaged with bone scans and PSMA PET performed within 100 d, were included for analysis. Each study was interpreted by 3 masked readers, and the results of the PSMA PET were used as the reference standard. Endpoints were positive predictive value (PPV), negative predictive value (NPV), and specificity for bone scans. Additionally, interreader reproducibility, positivity rate, uptake on PSMA PET, and the number of lesions were evaluated. Results: In total, 167 patients were included, with 77 at initial staging, 60 in the biochemical recurrence and castration-sensitive prostate cancer setting, and 30 in the castration-resistant prostate cancer setting. In all patients, the PPV, NPV, and specificity for bone scans were 0.73 (95% CI, 0.61-0.82), 0.82 (95% CI, 0.74-0.88), and 0.82 (95% CI, 0.74-0.88), respectively. In patients at initial staging, the PPV, NPV, and specificity for bone scans were 0.43 (95% CI, 0.26-0.63), 0.94 (95% CI, 0.85-0.98), and 0.80 (95% CI, 0.68-0.88), respectively. Interreader agreement for bone disease was moderate for bone scans (Fleiss κ, 0.51) and substantial for the PSMA PET reference standard (Fleiss κ, 0.80). Conclusion: In this multicenter retrospective study, the PPV of bone scans was low in patients at initial staging, with 57% of positive bone scans being false positives. This suggests that a large proportion of patients considered low-volume metastatic by the bone scan actually had localized disease, which is critical when applying clinical data from trials such as the STAMPEDE M1 radiation therapy trial to patients being staged with PSMA PET., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

68 Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on 68 Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Methods: 68 Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [ n = 10], colorectal cancer [ n = 10], pancreatic adenocarcinoma [ n = 10], genitourinary cancer [ n = 10], and other types of cancer [ n = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior 68 Ga-FAPI PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Results: Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. Conclusion: The interpretation of 68 Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: To evaluate the anatomic site(s) of initial disease progression in patients with castration resistant metastatic prostate cancer (mCRPC) in the presence or absence of pre-treatment visceral metastases while on systemic therapy., Methods: This is a retrospective cohort study of mCRPC patients who have baseline and at least one follow up bone scan and CT chest, abdomen and pelvis (CAP). Disease progression was determined by RECIST and/or ≥ 30% increase in automated bone scan lesion area score. Kaplan-Meier plot was used to estimate the median progression free survival and log-rank tests were used to compare anatomic sites., Results: Of 203 patients, 61 (30%) had pre-treatment visceral metastases. Patients with baseline visceral disease were 1.5 times more likely to develop disease progression (HR = 1.53; 95% CI, 1.03-2.26). Disease progression was a result of worsening bone scan disease (42% (16/38)) versus visceral (32% (12/38)) or lymph node disease (3% (1/38)) by CT or a combination thereof (23% (9/38)). Median time to progression (TTP) did not differ by anatomic location of initial progression (p = 0.86). Development of new lesions occurred in 50% of those visceral patients with soft tissue only progression and was associated with a significantly longer TTP (3.1 months (2.8-4.3 months) than those with worsening of pre-existing lesions (1.8 months (1.6-2.7 months); p = 0.04., Conclusions: Patients with pre-treatment visceral metastases in mCRPC are more likely to experience disease progression of bone disease with the initial anatomic site of progression similar to those without baseline visceral involvement., (© 2022. The Author(s).)

The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of 68 Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Methods: Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. Results: The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) ( P < 0.001) but not between PSMA PET/CT and mpMRI ( P = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE ( P = 0.002) and SVI ( P = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. Conclusion: PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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.)

Introduction: This is a prospective, single-center trial in pediatric patients with sarcoma aiming to evaluate [ 18 F]FDG PET/CT as a tool for early response assessment to neoadjuvant chemotherapy (neo-CTX)., Methods: Bone or soft tissue sarcoma patients with (1) baseline [ 18 F]FDG PET/CT within 4 weeks prior to the start of neo-CTX (PET1), (2) early interim [ 18 F]FDG PET/CT (6 weeks after the start of neo-CTX (PET2), (3) evaluation of neo-CTX response by histology or MRI, and (4) definitive therapy after neo-CTX (surgery or radiation) were included. Semiquantitative PET parameters (SUVmax, SUVmean, SUVpeak, MTV and TLG) and their changes from PET1 to PET2 (ΔPET) were obtained. The primary endpoint was to evaluate the predictive value of PET1, PET2 and ΔPET parameters for overall survival (OS) and time to progression (TTP). The secondary outcome was to evaluate if [ 18 F]FDG PET/CT can predict the response to neo-CTX assessed by histopathology or MRI. Primary and secondary outcomes were also evaluated in a subpopulation of patients with bone involvement only., Results: Thirty-four consecutive patients were enrolled (10 females; 24 males; median age 15.1 years). 17/34 patients (50%) had osteosarcoma, 13/34 (38%) Ewing's sarcoma, 2/34 (6%) synovial sarcoma and 2/34 (6%) embryonal liver sarcoma. Median follow-up was 39 months (range 16-84). Eight of 34 patients (24%) died, 9/34 (27%) were alive with disease, and 17/34 (50%) had no evidence of residual/recurrent disease. Fifteen of 34 (44%) and 19/34 (56%) were responders and non-responders, respectively. PET2-parameters were associated with longer TTP (p < 0.02). ΔMTV was associated with tissue response to neo-CTX (p = 0.047). None of the PET1, PET2 or ΔPET parameters were associated with OS., Conclusion: [ 18 F]FDG PET/CT performed 6 weeks after the start of neo-CTX can serve as an early interim biomarker for TTP and pathologic response but not for OS in pediatric patients with sarcoma.

In light of the United States Food and Drug Administration (FDA) requirement of 21 CFR 212 current Good Manufacturing Practice (cGMP) for FDA-approved position emission tomography (PET) drugs, the University of California Los Angeles (UCLA) Biomedical Cyclotron (BMC) transformed from a pre-cGMP era academic cyclotron and radiochemistry facility to a current cGMP-compliant PET drug manufacturer. In this article, we share the financial and regulatory compliance aspects of the "transformation" required to develop a sustainable quality system to support the production of two PET drugs under Abbreviated New Drug Applications (ANDAs).

A clinical validation of the bone scan lesion area (BSLA) as a quantitative imaging biomarker was performed in metastatic castration-resistant prostate cancer (mCRPC). BSLA was computed from whole-body bone scintigraphy at baseline and week 12 posttreatment in a cohort of 198 mCRPC subjects (127 treated and 71 placebo) from a clinical trial involving a different drug from the initial biomarker development. BSLA computation involved automated image normalization, lesion segmentation, and summation of the total area of segmented lesions on bone scan AP and PA views as a measure of tumor burden. As a predictive biomarker, treated subjects with baseline BSLA [Formula: see text] had longer survival than those with higher BSLA ([Formula: see text] and [Formula: see text]). As a surrogate outcome biomarker, subjects were categorized as progressive disease (PD) if the BSLA increased by a prespecified 30% or more from baseline to week 12 and non-PD otherwise. Overall survival rates between PD and non-PD groups were statistically different ([Formula: see text] and [Formula: see text]). Subjects without PD at week 12 had longer survival than subjects with PD: median 398 days versus 280 days. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different prostate cancer drug treatments.

The interobserver agreement for 68 Ga-PSMA-11 PET/CT study interpretations in patients with prostate cancer is unknown. Methods: 68 Ga-PSMA-11 PET/CT was performed in 50 patients with prostate cancer for biochemical recurrence ( n = 25), primary diagnosis ( n = 10), biochemical persistence after primary therapy ( n = 5), or staging of known metastatic disease ( n = 10). Images were reviewed by 16 observers who used a standardized approach for interpretation of local (T), nodal (N), bone (Mb), or visceral (Mc) involvement. Observers were classified as having a low (<30 prior 68 Ga-PSMA-11 PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 6). Histopathology ( n = 25, 50%), post-external-beam radiation therapy prostate-specific antigen response ( n = 15, 30%), or follow-up PET/CT ( n = 10, 20%) served as a standard of reference. Observer groups were compared by overall agreement (% patients matching the standard of reference) and Fleiss' κ with mean and corresponding 95% confidence interval (CI). Results: Agreement among all observers was substantial for T (κ = 0.62; 95% CI, 0.59-0.64) and N (κ = 0.74; 95% CI, 0.71-0.76) staging and almost perfect for Mb (κ = 0.88; 95% CI, 0.86-0.91) staging. Level of experience positively correlated with agreement for T (κ = 0.73/0.66/0.50 for high/intermediate/low experience, respectively), N (κ = 0.80/0.76/0.64, respectively), and Mc staging (κ = 0.61/0.46/0.36, respectively). Interobserver agreement for Mb was almost perfect irrespective of prior experience (κ = 0.87/0.91/0.88, respectively). Observers with low experience, when compared with intermediate and high experience, demonstrated significantly lower median overall agreement (54% vs. 66% and 76%, P = 0.041) and specificity for T staging (73% vs. 88% and 93%, P = 0.032). Conclusion: The interpretation of 68 Ga-PSMA-11 PET/CT for prostate cancer staging is highly consistent among observers with high levels of experience, especially for nodal and bone assessments. Initial training on at least 30 patient cases is recommended to ensure acceptable performance., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

18 F-clofarabine, a nucleotide purine analog, is a substrate for deoxycytidine kinase (dCK), a key enzyme in the deoxyribonucleoside salvage pathway. 18 F-clofarabine might be used to measure dCK expression and thus serve as a predictive biomarker for tumor responses to dCK-dependent prodrugs or small-molecule dCK inhibitors, respectively. As a prerequisite for clinical translation, we determined the human whole-body and organ dosimetry of 18 F-clofarabine. Methods: Five healthy volunteers were injected intravenously with 232.4 ± 1.5 MBq of 18 F-clofarabine. Immediately after tracer injection, a dynamic scan of the entire chest was acquired for 30 min. This was followed by 3 static whole-body scans at 45, 90, and 135 min after tracer injection. Regions of interest were drawn around multiple organs on the CT scan and copied to the PET scans. Organ activity was determined and absorbed dose was estimated with OLINDA/EXM software. Results: The urinary bladder (critical organ), liver, kidney, and spleen exhibited the highest uptake. For an activity of 250 MBq, the absorbed doses in the bladder, liver, kidney, and spleen were 58.5, 6.6, 6.3, and 4.3 mGy, respectively. The average effective dose coefficient was 5.1 mSv. Conclusion: Our results hint that 18 F-clofarabine can be used safely in humans to measure tissue dCK expression. Future studies will determine whether 18 F-clofarabine may serve as a predictive biomarker for responses to dCK-dependent prodrugs or small-molecule dCK inhibitors., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

We evaluated observer agreement for 68 Ga-DOTATATE PET/CT interpretations in patients with neuroendocrine tumor (NET)., Methods: 68 Ga-DOTATATE PET/CT was performed on 50 patients with known or suspected NET of the small bowel (n = 19), pancreas (n = 14), lung (n = 4), or other location (n = 13). The images were reviewed by 7 observers, who used a standardized interpretation approach. The observers were classified as having a low level of experience (<500 scans or <5 y experience with 68 Ga-DOTATATE PET/CT; n = 4) or a high level of experience (≥500 scans or ≥5 y experience with 68 Ga-DOTATATE PET/CT; n = 3). Interpretation by the primary nuclear medicine physician, who had access to all clinical and imaging data, served as the reference standard. Interobserver agreement was determined by the Cohen κ statistic and intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (95%CI)., Results: Interobserver agreement was substantial, and the median number of false findings was low for the overall scan result: that is, positive versus negative scan result (κ = 0.80; 95%CI, 0.74-0.86; false findings, 3), organ involvement (κ = 0.70; 95%CI, 0.64-0.76; false findings, 5), and lymph node involvement (κ = 0.71; 95%CI, 0.65-0.78; false findings, 6). Interobserver agreement was substantial to almost perfect, and the average absolute difference (Δ) from the reference observer was low for number of organ and lymph node metastases (organ: ICC, 0.84; 95%CI, 0.77-0.89; Δ = 0.45; lymph node: ICC, 0.77; 95%CI, 0.69-0.84; Δ = 0.45), tumor SUV max (ICC, 0.99; 95%CI, 0.97-0.99; Δ = 0.44), and reference SUV (spleen: ICC, 0.81; Δ = 1.10; liver: ICC, 0.79; Δ = 0.62). Interpretations of appropriateness for peptide-receptor radionuclide therapy varied more significantly among observers (κ = 0.64; 95%CI, 0.57-0.70), and a higher frequency of false-positive recommendations for peptide-receptor radionuclide therapy occurred in observers with low experience than in those with high experience (range, 7-12 vs. 4-8)., Conclusion: The interpretation of 68 Ga-DOTATATE PET/CT images for NET staging is consistent among observers with low and high levels of experience. However, image-based recommendations for or against peptide-receptor radionuclide therapy require experience and training., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

High-grade gliomas are aggressive cancers that often become rapidly fatal. Immunotherapy using CD8 + cytotoxic T lymphocytes (CTLs), engineered to express both herpes simplex virus type 1 thymidine kinase (HSV1-TK) and interleukin-13 (IL-13) zetakine chimeric antigen receptor (CAR), is a treatment strategy with considerable potential. To optimize this and related immunotherapies, it would be helpful to monitor CTL viability and trafficking to glioma cells. We show that noninvasive positron emission tomography (PET) imaging with 9-[4-[ 18 F]fluoro-3-(hydroxymethyl)butyl]guanine ([ 18 F]FHBG) can track HSV1-tk reporter gene expression present in CAR-engineered CTLs. [ 18 F]FHBG imaging was safe and enabled the longitudinal imaging of T cells stably transfected with a PET reporter gene in patients. Further optimization of this imaging approach for monitoring in vivo cell trafficking should greatly benefit various cell-based therapies for cancer., Competing Interests: Drs. C. Brown and M. Jensen are inventors on patent application WO 02/088334 held by City of Hope National Medical Center that covers Chimeric Immunoreceptor Useful in Treating Human Cancers. Drs. Yaghoubi and Gambhir are co-founders and equity holders of CellSight Inc. that develops strategies to image cell therapies in humans. Dr. Michael Jensen is on the scientific advisory board and equity holder of Juno Therapeutics, which develops novel cancer immunotherapies., (Copyright © 2017, American Association for the Advancement of Science.)

Background: The clinical significance of incidental thyroid abnormalities discovered in fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) (FDG PET/CT) studies remains controversial. The aim of this large retrospective study was to (a) determine the prevalence of focal F-FDG thyroid uptake on whole-body F-FDG PET/CT studies carried out for nonthyroid cancers and (b) to test whether intense focal F-FDG thyroid uptake is associated with malignancy., Materials and Methods: A total of 11 921 F-FDG PET/CT studies in 6216 patients carried out at our institution between January 2012 and December 2014 were analyzed. We retrospectively reviewed the medical records of these patients. Eight hundred and forty-five/6216 (13.6%) patients had a thyroid incidentaloma on the basis of the clinical F-FDG PET/CT report. One hundred and sixty/845 (18.9%) of these underwent ultrasound and 98 (61.3%) of these underwent a fine-needle aspiration (FNA). Twenty-six of these 98 (26.5%) patients underwent thyroidectomy. Thyroid lesion and background standardized uptake value (SUVs) for each patient were measured upon review of the F-FDG PET/CT study. We measured maximum standardized uptake value (SUVmax), thyroid to background TL/TBG, thyroid to bloodpool TL/BP and thyroid to liver TL/L ratios in benign and malignant lesions. Receiver operating curves were calculated to determine optimal cut-off values between malignant and benign lesions., Results: Twenty-one of the 98 patients who underwent FNA biopsy or thyroidectomy had malignant disease (21.4%). Malignant lesions had significantly higher thyroid lesion SUVmax, TL/TBG, TL/BP, and TL/L than benign nodules. The receiver operating curves derived cut-off ratio TL/TBG of more than 2.0 differentiated benign from malignant lesions best with a specificity and sensitivity of 0.76 and 0.88, respectively., Conclusion: The incidence of malignancy in biopsied focal hypermetabolic thyroid lesions is 21.4%. Lesions on F-FDG PET/CT studies, with a ratio TL/TBG more than 2.0, warrant further work-up with ultrasound and FNA to exclude malignancy.

Unlabelled: Brain metastases are frequently treated with radiation. It is critical to distinguish recurrent or progressive brain metastases (RPBM) from late or delayed radiation injury (LDRI). The purpose of this study was to examine the diagnostic accuracy as well as the prognostic power of 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) PET for differentiating RPBM from LDRI., Methods: Thirty-two patients who had 83 previously irradiated brain metastases and who underwent (18)F-FDOPA PET because of an MR imaging-based suggestion of RPBM were studied retrospectively. PET studies were analyzed semiquantitatively (lesion-to-striatum and lesion-to-normal brain tissue ratios based on both maximum and mean standardized uptake values) and visually (4-point scale). The diagnostic accuracy of PET was verified by histopathologic analysis (n = 9) or clinical follow-up (n = 74) on a lesion-by-lesion basis. Receiver operating characteristic curve analysis was used to identify the best diagnostic indices. The power of (18)F-FDOPA PET to predict disease progression was evaluated with the Kaplan-Meier and Cox regression methods., Results: The best overall accuracy was achieved by visual scoring, with which a score of 2 or more (lesion uptake greater than or equal to striatum uptake) resulted in a sensitivity of 81.3% and a specificity of 84.3%. Semiquantitative (18)F-FDOPA PET uptake indices based on lesion-to-normal brain tissue ratios were significantly higher for RPBM than for LDRI. Among the various predictors tested, (18)F-FDOPA PET was the strongest predictor of tumor progression (hazard ratio, 6.26; P < 0.001), and the lesion-to-normal brain tissue ratio or visual score was the best discriminator. The mean time to progression was 4.6 times longer for lesions with negative (18)F-FDOPA PET results than for lesions with positive (18)F-FDOPA PET results (76.5 vs. 16.7 mo; P < 0.001). (18)F-FDOPA PET findings tended to predict overall survival., Conclusion: Metabolic imaging with (18)F-FDOPA PET was useful for differentiating RPBM from LDRI. Semiquantitative indices, particularly lesion-to-normal uptake ratios, could be used. A visual score comparing tumor (18)F-FDOPA uptake and striatum (18)F-FDOPA uptake provided the highest sensitivity and specificity and was predictive of disease progression.

[¹⁸F]Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scans provide patients and referring physicians with diagnostic PET and CT information in a single imaging session. Because most lymphomas show high glucose metabolic activity and FDG avidity, they can be reliably assessed with FDG-PET/CT. PET/CT has emerged as the modality of choice for treatment strategy assessments in patients with lymphoma. Its ability to characterize masses as benign or malignant and its high sensitivity and specificity for staging, restaging, and treatment monitoring have led to widespread acceptance of PET imaging for managing patients with lymphoma., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The discovery of the Warburg effect in the early twentieth century followed by the development of the fluorinated glucose analogue 18 F-fluorodeoxyglucose ( 18 F-FDG) and the invention of positron emission tomographs laid the foundation of clinical PET/CT. This review discusses the challenges and obstacles in clinical adoption of this technique. We then discuss advances in instrumentation, including the critically important introduction of PET/CT and current PET/CT protocols. Moreover, we provide evidence for the clinical utility of PET/CT for patient management and its potential impact on patient outcome, and address its cost and cost-effectiveness. Although this review largely focuses on 18 F-FDG imaging, we also discuss a variety of additional molecular imaging approaches that can be used for cancer phenotyping with PET. Throughout this review we emphasize the critical contributions of CT to the strength of PET/CT.

Unlabelled: Oncologic (18)F-FDG PET/CT is rapidly gaining acceptance in clinical practice. However, the referring physician's attitude toward the usefulness of this diagnostic modality is unknown. This survey was undertaken to collect information regarding the current perspective of referring physicians on oncologic PET/CT., Methods: We conducted a prospective worldwide, Web-based survey of physicians who manage cancer patients. A total of 963 referring physicians completed a 20-question survey focused on their experience with oncologic (18)F-FDG PET/CT. Attention was directed toward their confidence about indications, their satisfaction with related educational resources, the quality of interaction with interpreting physicians, and practical problems encountered. The respondents included oncologists (38.5%, n = 371), hematologists (16.4%, n = 158), radiation oncologists (9.0%, n = 87), surgeons (30.3%, n = 292), and other physicians (5.7%, n = 55)., Results: Only 25.2% of respondents considered the oncologic (18)F-FDG PET/CT indications to be well established and defined. Frequent uncertainty about the need for a PET scan was indicated by 62.3% of the respondents. High cost and overinterpretation of findings were the most commonly reported concerns (47.0% and 40.9%, respectively). The experience and skill level of the interpreting physician was considered very important by 96.8% of the surveyed physicians., Conclusion: Referring physicians expressed considerable uncertainty about the appropriate use of oncologic PET/CT. Additional major concerns are procedure costs and quality of interpretation. The responses suggest a strong need for efforts to educate referring and interpreting physicians about the appropriate use of (18)F-FDG PET/CT in oncology.

Squamous papilloma is one of the most common benign neoplasms of the oral cavity and oropharynx. The (18)F-FDG PET/CT metabolic phenotype of this entity has not been described. We document the incidental finding of a hypermetabolic lesion at the right base of the tongue on an FDG PET/CT that proved to be squamous papilloma. The maximum standard uptake value was high at 7.0 g/ml. We conclude that oral cavity squamous papilloma can present with an intensely hypermetabolic phenotype on (18)F- FDG PET/CT. This benign entity should be included in the differential diagnosis of FDG-positive oral and oropharyngeal lesions.

Objective: The development and evaluation of a computer-aided bone scan analysis technique to quantify changes in tumor burden and assess treatment effects in prostate cancer clinical trials., Methods: We have developed and report on a commercial fully automated computer-aided detection (CAD) system. Using this system, scan images were intensity normalized, and then lesions were identified and segmented by anatomic region-specific intensity thresholding. Detected lesions were compared against expert markings to assess the accuracy of the CAD system. The metrics Bone Scan Lesion Area, Bone Scan Lesion Intensity, and Bone Scan Lesion Count were calculated from identified lesions, and their utility in assessing treatment effects was evaluated by analyzing before and after scans from metastatic castration-resistant prostate cancer patients: 10 treated and 10 untreated. In this study, patients were treated with cabozantinib, a MET/vascular endothelial growth factor inhibitor resulting in high rates of resolution of bone scan abnormalities., Results: Our automated CAD system identified bone lesion pixels with 94% sensitivity, 89% specificity, and 89% accuracy. Significant differences in changes from baseline were found between treated and untreated groups in all assessed measurements derived by our system. The most significant measure, Bone Scan Lesion Area, showed a median (interquartile range) change from baseline at week 6 of 7.13% (27.61) in the untreated group compared with -73.76% (45.38) in the cabozantinib-treated group (P=0.0003)., Conclusion: Our system accurately and objectively identified and quantified metastases in bone scans, allowing for interpatient and intrapatient comparison. It demonstrates potential as an objective measurement of treatment effects, laying the foundation for validation against other clinically relevant outcome measures.

Purpose: Many children with sarcomas undergo whole body 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and technetium methylene diphosphonate ((99)Tc-MDP) studies. It is unknown whether the combination of both tests results in more accurate detection of bone lesions than (18)F-FDG- PET/CT alone., Methods: (99)Tc-MDP bone and (18)F-FDG PET/CT scans were each read by 2 "blinded" observers and then reviewed side-by-side by 3 readers. Bone lesions were graded qualitatively on a 5-point scale (from benign to malignant). Clinical and imaging follow-up (n = 21) and bone biopsy results (n = 8) served as reference standard., Results: A total of 39 paired (99)Tc-MDP and (18)F-FDG-PET/CT studies (cases) performed at a mean interval 4 ± 7 days, were performed on 29 patients (mean age 12 ± 5 y). Of these, 21 patients (72%) had bone sarcoma, whereas 8 patients (28%) had soft tissue sarcoma. By patient and case-based analysis, (18)F-FDG PET/CT had an accuracy of 100%. Tc-MDP had accuracies of 90% and 82% by patient and case-based analysis. The combined interpretation had an accuracy of 97%., Conclusions: In this study, (99)Tc-MDP bone imaging does not provide an added diagnostic value for bone involvement over (18)F-FDG-PET/CT.