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Better biomarkers are needed to predict treatment outcome in non-small cell lung cancer (NSCLC) patients treated with anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors. PD-L1 immunohistochemistry has limited predictive value, possibly because of tumor heterogeneity of PD-L1 expression. Noninvasive PD-L1 imaging using 89 Zr-durvalumab might better reflect tumor PD-L1 expression. Methods: NSCLC patients eligible for second-line immunotherapy were enrolled. Patients received 2 injections of 89 Zr-durvalumab: one without a preceding dose of unlabeled durvalumab (tracer dose only) and one with a preceding dose of 750 mg of durvalumab, directly before tracer injection. Up to 4 PET/CT scans were obtained after tracer injection. After imaging acquisition, patients were treated with 750 mg of durvalumab every 2 wk. Tracer biodistribution and tumor uptake were visually assessed and quantified as SUV, and both imaging acquisitions were compared. Tumor tracer uptake was correlated with PD-L1 expression and clinical outcome, defined as response to durvalumab treatment. Results: Thirteen patients were included, and 10 completed all scheduled PET scans. No tracer-related adverse events were observed, and all patients started durvalumab treatment. Biodistribution analysis showed 89 Zr-durvalumab accumulation in the blood pool, liver, and spleen. Serial imaging showed that image acquisition 120 h after injection delivered the best tumor-to-blood pool ratio. Most tumor lesions were visualized with the tracer dose only versus the coinjection imaging acquisition (25% vs. 13.5% of all lesions). Uptake heterogeneity was observed within (SUV peak range, 0.2-15.1) and between patients. Tumor uptake was higher in patients with treatment response or stable disease than in patients with disease progression according to RECIST 1.1. However, this difference was not statistically significant (median SUV peak , 4.9 vs. 2.4; P = 0.06). SUV peak correlated better with the combined tumor and immune cell PD-L1 score than with PD-L1 expression on tumor cells, although neither was statistically significant ( P = 0.06 and P = 0.93, respectively). Conclusion: 89 Zr-durvalumab was safe, without any tracer-related adverse events, and more tumor lesions were visualized using the tracer dose-only imaging acquisition. 89 Zr-durvalumab tumor uptake was higher in patients with a response to durvalumab treatment but did not correlate with tumor PD-L1 immunohistochemistry., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

16α- 18 F-fluoro-17β-estradiol ( 18 F-FES) is a PET tracer characterizing the expression of the estrogen receptor (ER). Because therapy can interfere with the kinetics and biodistribution of 18 F-FES, the aim of this study was to describe the biodistribution of 18 F-FES in patients with metastatic ER-positive (ER+) breast cancer undergoing treatment with rintodestrant (G1T48), a novel selective ER degrader. Methods: Eight patients underwent 18 F-FES PET/CT imaging at baseline, 4-6 wk during treatment with rintodestrant (interim), and after treatment. After intravenous administration of 200 MBq (±10%) of 18 F-FES, a 50-min dynamic PET/CT scan of the thorax was obtained, followed by a whole-body PET/CT scan 60 min after injection. Blood samples were drawn for measuring whole blood and plasma activity concentration and the parent fraction of 18 F-FES. Volumes of interest were placed in the aorta ascendens and in healthy tissues on both dynamic and whole-body PET scans. SUVs and target-to-blood ratios (TBRs) were calculated. Areas under the curve (AUCs) of input functions and time-activity curves were calculated as a measure of uptake in different regions. Results: 18 F-FES concentration in whole blood (and plasma) significantly ( P < 0.05) increased at interim with median AUCs of 96.6, 116.6, and 110.3 at baseline, interim, and after treatment, respectively. In ER-expressing tissues, that is, the uterus and the pituitary gland, both SUV and TBR showed high 18 F-FES uptake at baseline, followed by a decrease in uptake at interim (uterus: SUV -50.6% and TBR -58.5%; pituitary gland: SUV -39.0% and TBR -48.3%), which tended to return to baseline values after treatment (uterus: SUV -21.5% and TBR -37.9%; pituitary gland: SUV -14.2% and TBR -26.0%, compared with baseline). In other healthy tissues, tracer uptake remained stable over the 3 time points. Conclusion: The biodistribution of 18 F-FES is altered in blood and in ER-expressing healthy tissues during therapy with rintodestrant. This indicates that rintodestrant alters the kinetics of the tracer, possibly affecting interpretation and quantification of 18 F-FES uptake. Of note, 6 d or more after treatment with rintodestrant ended, the biodistribution returned to baseline values, consistent with recovery of ER availability after washout of the drug., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

The tumor programmed death ligand 1 (PD-L1) proportion score is the current method for selecting non-small cell lung cancer (NSCLC) patients for single-agent treatment with pembrolizumab, a programmed cell death 1 (PD-1) monoclonal antibody. However, not all patients respond to therapy. Better understanding of in vivo drug behavior may help in the selection of patients who will benefit the most. Methods: NSCLC patients eligible for pembrolizumab monotherapy as first- or later-line therapy were enrolled. Patients received 2 injections of 89 Zr-pembrolizumab, 1 without a preceding dose of pembrolizumab and 1 with a preceding dose of 200 mg of pembrolizumab, directly before tracer injection. Up to 4 PET/CT scans were obtained after tracer injection. After imaging acquisition, patients were treated with 200 mg of pembrolizumab every 3 wk. Tumor uptake and tracer biodistribution were visually assessed and quantified as the SUV. Tumor tracer uptake was correlated with PD-1 and PD-L1 expression and response to pembrolizumab treatment. Results: Twelve NSCLC patients were included. One patient experienced grade 3 myalgia after tracer injection. 89 Zr-pembrolizumab was observed in the blood pool, liver, and spleen. Tracer uptake was visualized in 47.2% of 72 tumor lesions measuring ΒΧΡ20 mm in the long-axis diameter, and substantial uptake heterogeneity was observed within and between patients. Uptake was higher in patients with a response to pembrolizumab treatment ( n = 3) than in patients without a response ( n = 9), although this finding was not statistically significant (median SUV peak , 11.4 vs. 5.7; P = 0.066). No significant correlations were found with PD-L1 or PD-1 immunohistochemistry. Conclusion: 89 Zr-pembrolizumab injection was safe, with only 1 grade 3 adverse event-possibly immune-related-in 12 patients. 89 Zr-pembrolizumab tumor uptake was higher in patients with a response to pembrolizumab treatment but did not correlate with PD-L1 or PD-1 immunohistochemistry., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Metabolic tumor volume (MTV) on interim PET (I-PET) is a potential prognostic biomarker for diffuse large B-cell lymphoma (DLBCL). Implementation of MTV on I-PET requires a consensus on which semiautomated segmentation method delineates lesions most successfully with least user interaction. Methods used for baseline PET are not necessarily optimal for I-PET because of lower lesional SUVs at I-PET. Therefore, we aimed to evaluate which method provides the best delineation quality for Deauville score (DS) 4-5 DLBCL lesions on I-PET at the best interobserver agreement on delineation quality and, second, to assess the effect of lesional SUV max on delineation quality and performance agreement. Methods: DS 4-5 lesions from 45 I-PET scans were delineated using 6 semiautomated methods: a fixed SUV threshold of 2.5 g/cm 3 , a fixed SUV threshold of 4.0 g/cm 3 , an adaptive threshold corrected for source-to-local background activity contrast at 50% of the SUV peak , 41% of SUV max per lesion, a majority vote including voxels detected by at least 2 methods, and a majority vote including voxels detected by at least 3 methods (MV3). Delineation quality per MTV was rated by 3 independent observers as acceptable or nonacceptable. For each method, observer scores on delineation quality, specific agreement, and MTV were assessed for all lesions and per category of lesional SUV max (<5, 5-10, >10). Results: In 60 DS 4-5 lesions on I-PET, MV3 performed best, with acceptable delineation in 90% of lesions and a positive agreement of 93%. Delineation quality scores and agreement per method strongly depended on lesional SUV: the best delineation quality scores were obtained using MV3 in lesions with an SUV max of less than 10 and using SUV4.0 in more 18 F-FDG-avid lesions. Consequently, overall delineation quality and positive agreement improved by applying the most preferred method per SUV category instead of using MV3 as the single best method. The MV3- and SUV4.0-derived MTVs of lesions with an SUV max of more than 10 were comparable after exclusion of visually failed MV3 contouring. For lesions with an SUV max of less than 10, MTVs using different methods correlated poorly. Conclusion: On I-PET, MV3 performed best and provided the highest interobserver agreement regarding acceptable delineations of DS 4-5 DLBCL lesions. However, delineation-method preference strongly depended on lesional SUV. Therefore, we suggest exploration of an approach that identifies the optimal delineation method per lesion as a function of tumor 18 F-FDG uptake characteristics, that is, SUV max ., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

In prostate cancer (PCa) patients, the tumor-to-blood ratio (TBR) has been validated as the preferred simplified method for lesional 18 F-DCFPyL (a radiolabeled prostate-specific membrane antigen ligand) uptake quantification on PET. In contrast to SUVs, the TBR accounts for variability in arterial input functions caused by differences in total tumor burden between patients (the sink effect). However, TBR depends strongly on tracer uptake interval and has worse repeatability and is less applicable in clinical practice than SUVs. We investigated whether SUV could provide adequate quantification of 18 F-DCFPyL uptake on PET/CT in a patient cohort with low PCa burden. Methods: In total, 116 patients with PCa undergoing 18 F-DCFPyL PET/CT imaging were retrospectively included. All 18 F-DCFPyL-avid lesions suspected of being PCa were semiautomatically delineated. SUV peak was plotted against TBR for the most intense lesion of each patient. The correlation of SUV peak and TBR was evaluated using linear regression and was stratified for patients undergoing PET/CT for primary staging, patients undergoing restaging at biochemical recurrence, and patients with metastatic castration-resistant PCa. Moreover, the correlation was evaluated as a function of tracer uptake time, prostate-specific antigen level, and PET-positive tumor volume. Results: In total, 436 lesions were delineated (median, 1 per patient; range, 1-66). SUV peak correlated well with TBR in patients with PCa and a total tumor volume of less than 200 cm 3 ( R 2 = 0.931). The correlation between SUV and TBR was not affected by disease setting, prostate-specific antigen level, or tumor volume. SUV peak depended less on tracer uptake time than did TBR. Conclusion: For 18 F-DCFPyL PET/CT, SUV peak correlates strongly with TBR. Therefore, it is a valuable simplified, semiquantitative measurement in patients with low-volume PCa (<200 cm 3 ). SUV peak can therefore be applied in 18 F-DCFPyL PET assessment as an imaging biomarker to characterize tumors and to monitor treatment outcomes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Since the introduction of radiolabeled prostate-specific membrane antigen (PSMA) PET/CT, the ability to visualize recurrent prostate cancer has improved substantially. However, diagnostic accuracy is largely lacking for radiolabeled PSMA PET/CT in patients with biochemical persistence (BCP; that is, persistently measurable prostate-specific antigen [PSA] values after robot-assisted laparoscopic radical prostatectomy [RARP]). Therefore, the aim of this study was to determine the role of PSMA (i.e., 18 F-DCFPyL or 68 Ga-PSMA-11) PET/CT imaging in patients who experience BCP after RARP and to evaluate the sites of persistent disease on PSMA PET/CT. Methods: In total, 150 consecutive patients with BCP after RARP who underwent radiolabeled PSMA PET/CT imaging were retrospectively evaluated. BCP was defined as any detectable first serum PSA value after RARP (≥0.1 ng/mL) at least 6 wk after surgery, in the absence of an undetectable PSA value after RARP. A multivariable logistic regression analysis was performed to identify predictors for the detection of metastases outside the prostatic fossa (≥miN1) on PSMA PET/CT. Results: PSMA PET/CT was performed at a median PSA value of 0.60 ng/mL (interquartile range, 0.3-2.4) after a median of 6 mo (interquartile range, 4-10) after RARP. In total, 101 of 150 patients (67%) had lesions with PSMA expression on PET/CT, and 89 of 150 (59%) had lesions with increased PSMA expression sites outside the prostatic fossa. Moreover, 39 of 150 patients (26%) had PSMA-positive lesions outside the pelvis. On multivariable analysis, higher PSA values after RARP ( P = 0.004) and positive pathologic lymph node status ( P = 0.006) were independent predictors for ≥miN1. Conclusion: In the presence of BCP, a high proportion of patients already had disease metastatic to the pelvic lymph nodes or showed evidence of distant metastases, as indicated by PSMA PET/CT. Higher PSA levels after RARP and positive pathologic lymph node status were significantly associated with metastases outside the prostatic fossa. In patients with BCP, PSMA PET/CT imaging is warranted to guide salvage treatment strategies., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The identification of molecular drivers of disease and the compelling rise of biotherapeutics have impacted clinical care but have also come with challenges. Such therapeutics include peptides, monoclonal antibodies, antibody fragments and nontraditional binding scaffolds, activatable antibodies, bispecific antibodies, immunocytokines, antibody-drug conjugates, enzymes, polynucleotides, and therapeutic cells, as well as alternative drug carriers such as nanoparticles. Drug development is expensive, attrition rates are high, and efficacy rates are lower than desired. Almost all these drugs, which in general have a long residence time in the body, can stably be labeled with 89 Zr for whole-body PET imaging and quantification. Although not restricted to monoclonal antibodies, this approach is called 89 Zr-immuno-PET. This review summarizes the state of the art of the technical aspects of 89 Zr-immuno-PET and illustrates why it has potential for steering the design, development, and application of biologic drugs. Appealing showcases are discussed to illustrate what can be learned with this emerging technology during preclinical and especially clinical studies about biologic drug formats and disease targets. In addition, an overview of ongoing and completed clinical trials is provided. Although 89 Zr-immuno-PET is a young tool in drug development, its application is rapidly expanding, with first clinical experiences giving insight on why certain drug-target combinations might have better perspectives than others., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The aim of this work was to quantify the uptake of 18 F-BMS-986192, a programmed cell death ligand 1 (PD-L1) adnectin PET tracer, in patients with non-small cell lung cancer. To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as SUV was investigated. Methods: Data from a study with 18 F-BMS-986192 in patients with advanced-stage non-small cell lung cancer eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of 18 F-BMS-986192, a 60-min dynamic PET/CT scan was started, followed by a 30-min whole-body PET/CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time-activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor-to-blood ratio as well as several SUV measures. Results: Twenty-two tumors in 9 patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 of 18 tumor time-activity curves. The distribution volume ( V T ) ranged from 0.4 to 4.8 mL⋅cm -3 Similar values were obtained with an image-derived input function. From the simplified measures, SUV normalized for body weight at 50 and 67 min after injection correlated best with V T , with an R 2 of more than 0.9. Conclusion: A single-tissue reversible model can be used to quantify tumor uptake of the PD-L1 PET tracer 18 F-BMS-986192. SUV at 60 min after injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. To assess its predictive value for response evaluation during programmed cell death protein 1 or PD-L1 immune checkpoint inhibition, further validation of SUV against V T based on an image-derived input function is recommended., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Biochemically recurrent prostate cancer (BCR) is the main indication to perform prostate-specific membrane antigen PET/CT. However, localizing BCR with prostate-specific membrane antigen PET/CT remains challenging in patients with low prostate-specific antigen (PSA) values. Here, we studied the impact of advanced PET image reconstruction methods on BCR localization and interobserver agreement with 18 F-DCFPyL PET/CT scans in patients with BCR and low PSA values. Methods: Twenty-four patients with BCR and a PSA level of less than 2.0 ng/mL were included. PET images were reconstructed with 4-mm voxels and 2-mm voxels, both with and without point-spread function. All scans were interpreted by 4 nuclear medicine physicians. Additionally, PET examinations of 5 patients with primary prostate cancer and confirmed absence of lymph node metastases (after lymph node dissection) were included, to assess the risk of introducing false-positive findings when using advanced reconstruction. Calculation of BCR localization rates (scan positivity) was based on consensus among our readers (≥3 readers regarding a scan positive for BCR), as well as the individual scan interpretations of the readers. Results: In the consensus analysis, BCR localization rates were not higher using advanced reconstruction (62.5%-66.7%) than using 4-mm reconstruction (62.5%). On the basis of individual readings, however, more scans were positive using 2-mm reconstruction (74.0%; 95% confidence interval [CI], 65.0%-82.9%) ( P = 0.027) and 2-mm reconstruction with point-spread function (75.0%; 95% CI, 66.2%-83.8%) ( P = 0.014) than 4-mm reconstruction (65.6%; 95% CI, 56.0%-75.3%). A higher number of lesions was detected on the 2-mm scans (median, 2 lesions; interquartile range, 1-3) than the 4-mm scans (median, 1; interquartile range, 0-3; P = 0.008). The advanced reconstruction methods did not increase interobserver agreement (80.6%-84.7%), compared with the 4-mm scans (75.7%, P = 0.08-0.25). In the patients with primary prostate cancer, an equal number of false-positive lesions was observed among the different reconstruction methods (overall, n = 13). Conclusion: Applying advanced image reconstruction for 18 F-DCFPyL PET/CT scans did not increase BCR localization in patients with BCR and low PSA values (reader consensus). Yet, the increased number of positive individual readings may imply that further development of image reconstruction methods holds potential to improve BCR localization. No improved interobserver agreement was observed with advanced reconstruction compared with standard 4-mm reconstruction., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiolabeled prostate-specific membrane antigen (PSMA) PET has demonstrated promising results for prostate cancer (PCa) imaging. Quantification of PSMA radiotracer uptake is desired as it enables reliable interpretation of PET images, use of PSMA uptake as an imaging biomarker for tumor characterization, and evaluation of treatment effects. The aim of this study was to perform a full pharmacokinetic analysis of 2-(3-(1-carboxy-5-[(6- 18 F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid ( 18 F-DCFPyL), a second-generation 18 F-labeled PSMA ligand. On the basis of the pharmacokinetic analysis (reference method), simplified methods for quantification of 18 F-DCFPyL uptake were validated. Methods: Eight patients with metastasized PCa were included. Dynamic PET acquisitions were performed at 0-60 and 90-120 min after injection of a median dose of 313 MBq of 18 F-DCFPyL (range, 292-314 MBq). Continuous and manual arterial blood sampling provided calibrated plasma tracer input functions. Time-activity curves were derived for each PCa metastasis, and 18 F-DCFPyL kinetics were described using standard plasma input tissue-compartment models. Simplified methods for quantification of 18 F-DCFPyL uptake (SUVs; tumor-to-blood ratios [TBRs]) were correlated with kinetic parameter estimates obtained from full pharmacokinetic analysis. Results: In total, 46 metastases were evaluated. A reversible 2-tissue-compartment model was preferred for 18 F-DCFPyL kinetics in 59% of the metastases. The observed k 4 was small, however, resulting in nearly irreversible kinetics during the course of the PET study. Hence, k 4 was fixated (0.015) and net influx rate, K i , was preferred as the reference kinetic parameter. Whole-blood TBR provided an excellent correlation with K i from full kinetic analysis ( R 2 = 0.97). This TBR could be simplified further by replacing the blood samples with an image-based, single measurement of blood activity in the ascending aorta (image-based TBR, R = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. 2 = 0.96). SUV correlated poorly with K i ( R 2 = 0.47 and R 2 = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. Conclusion: 18 F-DCFPyL kinetics in PCa metastases are best described by a reversible 2-tissue-compartment model. Image-based TBRs were validated as a simplified method to quantify 18 F-DCFPyL uptake and might be applied to clinical, whole-body PET scans. SUV does not provide reliable quantification of 18 F-DCFPyL uptake., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

PET is increasingly used for prostate cancer (PCa) diagnostics. Important PCa radiotracers include 68 Ga-prostate-specific membrane antigen HBED-CC ( 68 Ga-PSMA), 18 F-DCFPyL, 18 F-fluoromethylcholine ( 18 F-FCH), and 18 F-dihydrotestosterone ( 18 F-FDHT). Knowledge on the variability of tracer uptake in healthy tissues is important for accurate PET interpretation, because malignancy is suspected only if the uptake of a lesion contrasts with its background. Therefore, the aim of this study was to quantify uptake variability of PCa tracers in healthy tissues and identify stable reference regions for PET interpretation. Methods: A total of 232 PCa PET/CT scans from multiple hospitals was analyzed, including 87 68 Ga-PSMA scans, 50 18 F-DCFPyL scans, 68 18 F-FCH scans, and 27 18 F-FDHT scans. Tracer uptake was assessed in the blood pool, lung, liver, bone marrow, and muscle using several SUVs (SUV max , SUV mean , SUV peak ). Variability in uptake between patients was analyzed using the coefficient of variation (COV%). For all tracers, SUV reference ranges (95th percentiles) were calculated, which could be applicable as image-based quality control for future PET acquisitions. Results: For 68 Ga-PSMA, the lowest uptake variability was observed in the blood pool (COV, 19.9%), which was significantly more stable than all other tissues (COV, 29.8%-35.2%; P = 0.001-0.024). For 18 F-DCFPyL, the lowest variability was observed in the blood pool and liver (COV, 14.4% and 21.7%, respectively; P = 0.001-0.003). The least variable 18 F-FCH uptake was observed in the liver, blood pool, and bone marrow (COV, 16.8%-24.2%; P = 0.001-0.012). For 18 F-FDHT, low uptake variability was observed in all tissues, except the lung (COV, 14.6%-23.6%; P = 0.001-0.040). The different SUV types had limited effect on variability (COVs within 3 percentage points). Conclusion: In this multicenter analysis, healthy tissues with limited uptake variability were identified, which may serve as reference regions for PCa PET interpretation. These reference regions include the blood pool for 68 Ga-PSMA and 18 F-DCFPyL and the liver for 18 F-FCH and 18 F-FDHT. Healthy tissue SUV reference ranges are presented and applicable as image-based quality control., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)