Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived tumor xenografts (PDX). Inter- and intra-tumor heterogeneity of PDX, however, present several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics of FDG-PET to assess response to combination docetaxel/carboplatin therapy in a co-clinical trial involving triple negative breast cancer (TNBC) PDX. We characterize the reproducibility of SUV metrics to assess response to therapy and optimize a preclinical PERCIST (µPERCIST) paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size; solid tumor vs. tumor heterogeneity and necrotic phenotype; and optimal selection of tumor slice versus whole tumor. A test-retest protocol was implemented to optimize the reproducibility of FDG-PET SUV thresholds, SUVpeak metrics, and µPERCIST parameters. In assessing response to therapy, FDG-PET imaging was performed at baseline and +4 days following therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index—"Quantitative Response Assessment Score (QRAS)"—to integrate parameters of prediction and precision, and thus aid in selecting optimal image metrics of response to therapy. Our data suggests that a threshold value of 25% (SUV25) of SUVmax was highly reproducible (<9% variability). Concordance and reproducibility of µPERCIST were maximized at α=0.7 and β=2.8 and exhibited high correlation to SUV25 measures of tumor uptake. QRAS scores favor SUV25 followed by SUVP14 as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and µPERCIST SUVP14 as image metrics of response to therapy across a wide range of therapeutic regiments and PDX models.

Objectives: Lutetium-177 (¹⁷⁷Lu)-PSMA-617 (LuPSMA) is a radioligand with high affinity for prostate specific membrane antigen (PSMA) enabling targeted beta-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castrate-resistant prostate cancer (mCRPC). We now report their longer-term outcomes including a 20 patient extension cohort and outcomes of subsequent systemic treatments following completion of trial therapy. Methods: 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. Endpoints included PSA response (PCWG2), toxicity (CTCAE v4.03), imaging response, patient-reported health-related quality of life (QoL), progression-free and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including LuPSMA. Results: 75 men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 months) and extensive prior treatment including prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with ≥ 80% decrease. Of 27 patients with measurable soft tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to LuPSMA were self-limiting G1-2 dry mouth (66%), transient G1-2 nausea (48%), G3-4 thrombocytopenia (10%) and G3 anemia (10%). Brief pain inventory severity and interference scores decreased at all time points including at the 3 month follow-up with a decrease of -1.2 (95% CI -0.5 to -1.9, P = 0.001) and 1.0 (95% CI -0.2 to -0.18, P = 0.013), respectively. At a median follow-up of 31.4 months, median OS was 13.3 months (95% CI 10.5-18.7) with a significantly longer survival of 18.4 months (95% CI 13.8-23.8) in patients achieving a PSA decline ≥ 50%. At progression following prior response, further LuPSMA was administered to 15 (30%) patients (median 2 cycles commencing 359 days from enrolment) with PSA decline ≥ 50% in 11 patients (73%). 4 of 21 patients (19%) receiving other systemic therapies upon progression experienced PSA decline ≥ 50%. There were no unexpected adverse events with LuPSMA re-treatment. Conclusion: This expanded 50 patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity and improved QoL with LuPSMA radioligand therapy. Upon progression, re-challenge LuPSMA demonstrated higher response rates than other systemic therapies.

Purpose: Although the incidence of de novo neuroendocrine prostate cancer (NEPC) is rare, recent data suggests that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine (NE) hallmarks and androgen receptor (AR)-suppression in prostate cancer (PC). Previous clinical reports indicate that PCs with a phenotype similar to NE tumors can be more amenable to imaging by ¹⁸F-Fluorodeoxyglucose (FDG) rather than PSMA-targeting radioligands. In this study, we evaluated the association between NE gene signature and FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported FDG-avidity of PSMA-suppressed tumors. Methods: Data mining approaches, cell lines and patient-derived xenograft (PDX) models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes: HK1 to 3 and GCK) and PSMA (FOLH1 gene) following AR-inhibition and in correlation with NE hallmarks. Also, we characterize a NE-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no NE histopathology. We measured glucose uptake in a NE-induced in vitro model and a zebrafish model by non-radioactive imaging of glucose uptake using fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrates that a NE gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR-inhibitors, high expression of GCK and low expression of SLC2A12 correlated with NE histopathology and PSMA gene suppression. GLUT12-suppression and amplification of glucokinase was observed in NE-induced PC cell lines and PDX models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: NE gene signature in NEPC and NELPC associates with a distinct transcriptional profile of GLUTs and HKs. PSMA-suppression correlates with GLUT12-suppression and glucokinase-amplification. Alteration of FDG uptake-associated genes correlated positively with higher glucose uptake in AR and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient pre-clinical method for monitoring non-radioactive glucose uptake.

Due to their peculiar mechanism of action, the evaluation of radiological response to immune checkpoint inhibitors (ICI) presents many challenges in solid tumors. We aimed to compare the evaluation of first response to Nivolumab by means of CT-based criteria with respect to fluorodeoxyglucose positron emission tomography (FDG-PET) response criteria in non-small-cell lung cancer (NSCLC) patients. Methods: 72 patients with advanced NSCLC were recruited in a mono-institutional ancillary trial within the expanded access program (EAP; NCT02475382) for Nivolumab. Patients underwent CT scan and FDG-PET at baseline and after 4 cycles (first evaluation). In case of progressive disease (PD), an additional evaluation was performed after two further cycles in order to confirm progression. We evaluated the response to treatment with CT scan by means of response evaluation criteria in solid tumors (RECIST) 1.1 and Immuno-related Response Criteria (IrRC) and with FDG-PET by means of PERCIST and immunotherapy-modified-PERCIST (imPERCIST) criteria. The concordance between CT- and PET-based criteria and the capability of each method to predict overall survival (OS) were evaluated. Results: 48/72 patients were evaluable for first response assessment with both PET- and CT-based criteria. We observed low concordance between CT- and PET-based criteria (Kappa value of 0.346 and 0.355 and Kappa value of 0.128 and 0.198 between PERCIST and imPERCIST versus RECIST and irRC respectively). Looking at OS, IrRC were more reliable to distinguish responders from non-responders. However thanks to the prognostic value of partial metabolic response assessed by both PERCIST and Immuno-PERCIST, PET-based response maintained prognostic significant in patients classified as progressive disease on the basis of irRC. Conclusion: Even though the present study did not support the routine use of FDG-PET in the general population of NSCLC patients treated with ICI, it suggests the added prognostic value of the metabolic response assessment, potentially improving the therapeutic decision-making.

Objectives: The detection of cancer micrometastasis for early diagnosis and treatment poses a great challenge for conventional imaging techniques. The aim of study is to evaluate the performance of photoacoustic imaging (PAI) in detecting hepatic micrometastases from melanoma in a very early stage and perform tumor resection by intraoperative photoacoustic image-guidance. Methods: In vivo studies were performed by following protocols approved by the Ethical Committee for Animal Research at Xiamen University. First, a B16 melanoma hepatic metastasis mouse model (n = 10) was established to study the development of micrometastases in vivo. Next, the hepatic metastasis mice models were imaged by scalable PAI instrument, ultrasound, 9.4 T high-resolution magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and bioluminescence imaging. Photoacoustic images acquired with optical wavelengths spanning from 680 to 850 nm were spectrally unmixed by using a linear least-squares method to differentiate various components. Differences in the signal-to-background ratios among different modalities were determined with the two-tailed paired t test. The diagnosis results were assessed with histologic examinations. Excised liver samples from patients diagnosed with hepatic cancer were also examined to identify tumor boundary. In vivo metastatic melanoma removal in surgery was precisely guided by the portable PAI system. Results: PAI achieved as small as ~400 µm hepatic melanoma detection at a depth up to 7 mm in vivo, which could early detect small melanoma compared with ultrasound and MRI in mouse models. The signal ratio of tumor-to-liver acquired with PAI in micrometastases at 8 days (4.2 ± 0.2, n = 6) and 14 days (9.2 ± 0.4, n = 5) were significantly higher than those obtained with PET/CT (1.8 ± 0.1, n = 5 and 4.5 ± 0.2, n = 5, P <0.001 for both). Functional PAI provided dynamic oxygen saturation changes during tumor growth. The limit of detection was measured to be approximately 219 cells per microliter in vitro. We successfully performed intraoperative photoacoustic image-guided surgery in vivo using the rapid portable PAI system. Conclusion: Our findings offer a rapid and effective tool to noninvasively detect micrometastases and guide intraoperative resection as a complementary clinical imaging application.

Calculation of radiation dosimetry in targeted nuclear medicine therapies is traditionally resource-intensive requiring multiple post-therapy SPECT acquisitions. An alternative approach is to take advantage of existing pharmacokinetic data from these smaller cohorts to enable dose computation from a single post-treatment scan in a manner that may be applied to a much broader patient population. Methods: In this work, a technical description for simplified dose estimation is presented and applied to assessment of ¹⁷⁷Lu-PSMA-617 therapy (Prostate-Specific Membrane Antigen) for metastatic prostate cancer. By normalizing existing time-activity curves to a single measurement time, it is possible to calculate a mean and range of time-integrated activity values which relate to radiation absorbed dose. To assist with accurate pharmacokinetic modelling of the training cohort, a method for contour-guided image registration was developed. Results: Tissue-specific dose conversion factors for common post-treatment imaging times are reported along with a characterization of added uncertainty in comparison to a traditional serial imaging protocol. Single time point dose factors for tumor were determined to be 11.0, 12.1, 13.6, and 15.2 Gy per MBq/mL at image times of 24, 48, 72, and 96 hours, respectively. For normal tissues, parotid gland factors were 6.7, 9.4, 13.3, and 19.3 Gy per MBq/mL and kidneys were 7.1, 10.3, 15.0, and 22.0 Gy per MBq/mL at those times. Tumor dose estimates were most accurate using delayed scanning at times beyond 72 hours. Dose to healthy tissues is best characterized by scanning patients in the first two days of treatment owing to the larger degree of tracer clearance in this early phase. Conclusion: The work demonstrates a means for efficient dose estimation in ¹⁷⁷Lu-PSMA-617 therapy. By providing methods to simplify and potentially automate radiation dosimetry we hope to accelerate the understanding of radiobiology and development of dose-response models in this unique therapeutic context.

Introduction: The aim of this study was to analyze patterns of persistent versus recurrent or new PET lesions in a selected patient cohort with PSA persistence following salvage lymph node dissection (SLND) and pre/post procedure prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET). Material and Methods: 16 patients were included in this multicenter study. Inclusion criteria were: a) PSMA-PET performed for biochemical recurrence before SLND (pre-SLND PET) and b) repeat PSMA-PET performed for persistently elevated PSA level (≥0.1 ng/mL) ≥6 weeks after SLND (post-SLND PET). Image analysis was performed by three independent nuclear medicine physicians applying the molecular imaging TNM system PROMISE. Lesions were confirmed by histopathology, presence on correlative CT/MRI/bone scan or PSA response after focal therapy. Results: post-SLND PET identified PCa-lesions in 88% (14/16) of patients with PSA persistence after SLND. Median PSA was 1.2 ng/mL (IQR, 0.6-2.8 ng/mL). Disease was confined to the pelvis in 56% of patients (9/16) and most of these men had common iliac (6/16, 38%) and internal iliac lymph node metastases (6/16, 38%). Extrapelvic disease was detected in 31% of patients (5/16). In pre- and post-SLND PET comparison, 10/16 had at least one lesion already detected at baseline (63% PET persistence); 4/16 had new lesions only (25% PET recurrence); 2 had no disease on post-SLND PET. All validated regions (11 regions in 9 patients) were true positive. 9/14 (64%) patients underwent repeat local therapies after SLND (7/14 radiotherapy, 2/14 surgery). Conclusion: SLND of pelvic nodal metastases was often not complete according to PSMA-PET. About two thirds of patients had PET positive nodal disease after SLND already seen on pre-SLND PSMA-PET. Notably, about one quarter of patients had new lesions, not detected by pre-surgical PSMA-PET.

The PET radiotracer ⁶⁸Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA-11) shows potential as an imaging biomarker for recurrent and metastatic prostate cancer. The purpose of this study was to determine repeatability of ⁶⁸Ga-PSMA-HBED-CC in a test-retest trial in subjects with metastatic prostate adenocarcinoma. Methods: Subjects with metastatic prostate cancer underwent two PET/CT scans with ⁶⁸Ga-PSMA-HBED-CC within 14 days (mean 6 ± 4 d). Lesions in bone, nodes, prostate/bed, and visceral organs as well as representative normal tissues (salivary glands and spleen) were segmented separately by two readers. Absolute and percent differences in SUV_max and SUVmean were calculated for all test-retest regions. Repeatability was assessed using percentage difference, within-subject coefficient of variation (wCV), repeatability coefficient (RC), and Bland-Altman analysis. Results: 18 subjects were evaluated, 16 of which demonstrated local or metastatic disease on ⁶⁸Ga-PSMA-HBED-CC PET/CT. A total of 136 lesions were segmented in bone (n = 99), nodes (n = 27), prostate/bed (n = 7), and viscera (n = 3). The wCV for SUV_max was 11.7% for bone lesions and 13.7% for nodes. The RC was ±32.5% SUV_max for bone lesions and ±37.9% SUV_max for nodal lesions, meaning 95% of the normal variability between two measurements will be within these numbers, so larger differences are likely attributable to true biological changes in tumor rather than normal physiologic or measurement variability. wCV in the salivary glands and spleen was 8.9% and 10.7% SUVmean, respectively. Conclusion: Repeatability measurements for PET/CT test-retest with ⁶⁸Ga-PSMA-HBED-CC show a wCV 12-14% SUV_max and RC ±33-38% SUV_max in bone and nodal lesions. These estimates are an important aspect of ⁶⁸Ga-PSMA-HBED-CC as a quantitative imaging biomarker. These estimates are similar to those reported for ¹⁸F-FDG, suggesting that ⁶⁸Ga-PSMA-HBED-CC PET/CT may be useful in monitoring response to therapy.

P-glycoprotein (ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting the clearance of neurotoxic beta-amyloid (Aß) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease (AD) patients. Treatment with drugs which induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aß deposits in the brain by enhancing the clearance of Aß peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer ¹¹C-metoclopramide can measure ABCB1 induction at the BBB in a beta-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 days underwent ¹¹C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor (PXR) activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 days. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aß levels. In separate groups of mice, radiolabeled metabolites of ¹¹C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aß levels. There was a significant positive correlation between kE,brain values and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain values was found. Metabolite analysis showed that the majority of radioactivity in the brain was composed of unmetabolized ¹¹C-metoclopramide in all animal groups. Conclusion: ¹¹C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in AD patients to non-invasively evaluate strategies to enhance the clearance properties of the BBB.

Background: Accurate definition of the extent and severity of left-ventricular assist device (LVAD) infection may facilitate therapeutic decision making and targeted surgical intervention. Here, we explore the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for guidance of patient management. Methods: Fifty-seven LVAD-carrying patients received 85 whole-body ¹⁸F-FDG PET/CT scans for the work-up of device infection. Clinical follow-up was obtained over a period of up to two years. Results: PET/CT showed various patterns of infectious involvement of the 4 LVAD components: driveline entry point (77% of cases), subcutaneous driveline path (87%), pump pocket (49%) and outflow tract (58%). Driveline smears revealed staphylococcus or pseudomonas strains as the underlying pathogen in a majority of cases (48 and 34%, respectively). At receiver-operating characteristics analysis, an ¹⁸F-FDG standardized uptake value (SUV) >2.5 was most accurate to identify smear-positive driveline infection. Infection of 3 or all 4 LVAD components showed a trend towards lower survival vs infection of 2 or less components (P = 0.089), while involvement of thoracic lymph nodes was significantly associated with adverse outcome (P = 0.001 for nodal SUV above vs below median). Finally, patients that underwent early surgical revision within 3 months after PET/CT (n = 21) required significantly less inpatient hospital care during follow-up when compared to those receiving delayed surgical revision (n = 11; p<0.05). Conclusion: Whole-body ¹⁸F-FDG PET/CT identifies the extent of LVAD infection and predicts adverse outcome. Initial experience suggests that early image-guided surgical intervention may facilitate a less complicated subsequent course.

Cri-Du-Chat Syndrome (CdCs) is a rare genetic disease caused by a deletion in the short arm of chromosome 5 (5p) with a variable clinical spectrum. To date no study in literature has ever investigated the alterations of brain glucose metabolism in these subjects by means of [¹⁸F]fluoro-2-deoxy-d-glucose Positron Emission Tomography/Computed Tomography (¹⁸F-FDG PET/CT). The aims of this study were to detect difference in brain FDG metabolism in patients affected by CdCs with different clinical presentations and identify possible "brain metabolic phenotypes" of this syndrome. Methods: 6 patients (age: 5 M and 1 F, age range: 10-27) with CdCs were assessed for presence of cognitive and behavioral symptoms with a battery of neuropsychological tests and then classified as patient with a severe or mild phenotype. Then, patients underwent a brain ¹⁸F-FDG PET/CT scan. PET/CT findings were compared to a control group, matched for age and sex, by using statistical parametric mapping (SPM). Association of different clinical phenotypes and ¹⁸F-FDG PET/CT findings was investigated. Results: Four patients presented a severe phenotype, whereas 2 patients demonstrated mild phenotype. SPM single subject and group analysis compared to the control cohort revealed a significant hypometabolism in the left temporal lobe (BAs 20, 36 and 38), in the right frontal subcallosal gyrus (BA 34) and caudate body, and in the cerebellar tonsils (p<0.001). Hypermetabolism (P = 0.001) was revealed in the right superior and precentral frontal gyrus (BA 6) in patient group compared to the control cohort. In SPM single subject analysis the hypermetabolic areas were detected only in patients with a severe phenotype. Conclusion: This study revealed different patterns of brain glucose metabolism in patients with severe and mild phenotype compared to control subjects. In particular, the hypermetabolic abnormalities in the brain, evaluated by¹⁸F-FDG PET/CT, seem to correlate with the severe phenotype in patients with CdCs.

Background: Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy as they can constitute as much as 90% of tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP-inhibitor PET tracer, ⁶⁸Ga-FAPI-04, has been previously shown to yield high tumor-to-background ratios (TBR) in patients with various cancers. Recent developments towards an improved compound for therapeutic application have identified FAPI-46 as a promising agent due to a longer tumor retention time in comparison with FAPI-04. Here we present a PET biodistribution and radiation dosimetry study of ⁶⁸Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial ⁶⁸Ga-FAPI-46 PET/CT scans at three time points following radiotracer injection: 10 minutes, 1 hour, and 3 hours. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and body remainder. OLINDA/EXM v.1.1 software was used to fit and integrate the kinetic organ activity data to yield total body and organ time-integrated activity coefficients/residence times and finally organ absorbed doses. Standardized uptake values (SUV) and TBR were generated from the contoured tumor and source organ volumes. Spherical volumes in muscle and blood pool were also obtained for TBR (Tumor SUV_max / Organ SUVmean). Results: At all timepoints, the highest organ SUV_max was observed in the liver. Tumor and organ mean SUVs decreased whereas TBRs in all organs but the uterus increased with time. The highest TBRs at 3 hours were observed with the bone marrow (31.1), muscle (22.8), heart (19.1), and spleen (19.0). Organs with the highest effective doses were the bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04mSv/MBq). The average effective total body dose was 7.80E-03 mSv/MBq. Thus for administration of 200 MBq ⁶⁸Ga-FAPI-46 the effective total body dose is 1.56 mSv ± 0.26 mSv, in addition to approximately 3.7 mSv from one low-dose CT scan done for attenuation correction. Conclusion: ⁶⁸Ga-FAPI-46 PET/CT has a favorable dosimetry profile with an estimated whole body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of ⁶⁸Ga-FAPI-46 (1.56± 0.26 mSv from the PET tracer and 3.7 mSv from one low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

Due to improvements in quantitative SPECT/CT, voxel-based dosimetry for radionuclide therapies has aroused growing interest as it promises the visualization of absorbed doses at a voxel level. In this work, SPECT/CT-based voxel-based dosimetry of a 3D printed 2-compartment kidney phantom was performed, and the resulting absorbed dose distributions were examined. Additionally, the potential of the PETPVC partial-volume correction tool was investigated. Methods: Both kidney compartments (70% cortex, 30% medulla) were filled with different activity concentrations and SPECT/CT imaging was performed. The images were reconstructed using varying reconstruction settings (iterations, subsets, and post-filtering). Based on these activity concentration maps, absorbed dose distributions were calculated with pre-calculated ¹⁷⁷Lu voxel S values and an empirical kidney half-life. An additional set of absorbed doses was calculated after applying PETPVC for partial-volume correction of the SPECT reconstructions. Results: SPECT/CT imaging blurs the two discrete sub-organ absorbed dose values into a continuous distribution. While this effect is slightly improved by applying more iterations, it is enhanced by additional post-filtering. By applying PETPVC, the absorbed dose values are separated into 2 peaks. Although this leads to a better agreement between SPECT/CT-based and nominal values, considerable discrepancies remain. In contrast to the calculated nominal absorbed doses of 7.8/1.6 Gy (cortex/medulla), SPECT/CT-based voxel-level dosimetry resulted in mean absorbed doses ranging from 3.0-6.6 Gy (cortex) and 2.7-5.1 Gy (medulla). PETPVC led to improved ranges of 6.1-8.9 Gy (cortex) and 2.1-5.4 Gy (medulla). Conclusion: Our study shows that ¹⁷⁷Lu quantitative SPECT/CT imaging leads to voxel-based dose distributions largely differing from the real organ distribution. SPECT/CT imaging and reconstruction deficiencies might directly translate into unrealistic absorbed dose distributions, thus questioning the reliability of SPECT-based voxel-level dosimetry. Therefore, SPECT/CT reconstructions should be adapted to ensure an accurate quantification of the underlying activity and, therefore, absorbed dose in a volume-of-interest of the expected object size (e.g. organs, organ sub-structures, lesions or voxels). As an example, PETPVC largely improves the match between SPECT/CT-based and nominal dose distributions. In conclusion, the concept of voxel-based dosimetry should be treated with caution. Specifically, it should be kept in mind that the absorbed dose distribution is mainly a convolved version of the underlying SPECT reconstruction.

Purpose: To evaluate ¹¹C-choline PET/CT detection performance for biochemically recurrent prostate cancer (PCa) in a large non-European cohort in the context of emerging evidence for PSMA PET in this setting, and to map patterns of PCa recurrence. Methods: We retrospectively analyzed ¹¹C-choline PET/CT scans from 287 patients who were enrolled onto an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean:3.43 ng/mL, median:0.94 ng/mL, range:0.15–89.91) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP; 79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy (RT), and 70 had persistent PSA elevation after receiving initial treatment (69 post-RP, 1 post-RT). The level of suspicion for recurrence on ¹¹C-choline PET/CT was scored (0:negative, 1:equivocal, 2:positive) by two readers. The correlation between ¹¹C-choline PET/CT positivity and initial treatment, Gleason score, NCCN stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map ¹¹C-choline recurrence patterns. Results: Considering scores 1 and 2 as positives, consensus between the two readers deemed 66% of the ¹¹C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with PSA<0.5 ng/mL, 56% of patients with PSA 0.5–0.99 ng/mL, 70% of patients with PSA 1.0–1.99 ng/mL, and 90% of patients with PSA ≥2.0 ng/mL scored either 1 or 2 on ¹¹C-choline PET/CT scans. When considering scores of 2 only, ¹¹C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA <0.5 ng/mL, 0.5–0.99 ng/mL, 1.0–1.99 ng/mL, and ≥2.0 ng/mL). In multivariate analysis, only the PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had ¹¹C-choline-positive suspected recurrences outside the initial treatment field. Conclusion: ¹¹C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pre-test probability. Until PSMA agents are fully approved for PCa, choline PET/CT may provide clinical utility.

Prediction of post-operative pulmonary function in lung cancer patients before tumor resection is essential for patient selection for surgery and is conventionally done with a non-imaging segment counting method (SC) or a two-dimensional planar lung perfusion scintigraphy (PS). The purpose of this study was to compare quantitative analysis of PS to single photon emission computed tomography/computed tomography (SPECT/CT) and to estimate the accuracy of SC, PS and SPECT/CT in predicting post-operative pulmonary function in patients undergoing lobectomy. Methods: Seventy-five non-small cell lung cancer (NSCLC) patients planned for lobectomy were prospectively enrolled (68% males, average age 68.1±8 years ). All patients completed pre-operative forced expiratory volume capacity (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO), Tc99m-MAA lung perfusion scintigraphy with PS and SPECT/CT quantification. A subgroup of 60 patients underwent video-assisted thoracoscopic (VATS) lobectomy and measurement of post-operative FEV1 and DLCO. Relative uptake of the lung lobes estimated by PS and SPECT/CT were compared. Predicted post-operative FEV1 and DLCO were derived from SC, PS and SPECT/CT. Prediction results were compared between the different methods and the true post-operative measurements in patients who underwent lobectomy. Results: Relative uptake measurements differed significantly between PS and SPECT/CT in right lung lobes, with a mean difference of -8.2±3.8, 18.0±5.0 and -11.5±6.1 for right upper, middle and lower lobes respectively (p<0.001). The differences between the methods in the left lung lobes were minor with a mean difference of -0.4±4.4 (p>0.05) and -2.0±4.0 (p<0.001) for left upper and lower lobes respectively. No significant difference and strong correlation (R=0.6-0.76, p<0.001) were found between predicted post-operative lung function values according to SC, PS, SPECT/CT and the actual post-operative FEV1 and DLCO. Conclusion: Although lobar quantification parameters differed significantly between PS and SPECT/CT, no significant differences were found between the predicted post-operative lung function results derived from these methods and the actual post-operative results. The additional time and effort of SPECT/CT quantification may not have an added value in patient selection for surgery. SPECT/CT may be advantageous in patients planned for right lobectomies but further research is warranted.

Introduction: A new pattern of response, so-called hyper-progressive disease (HPD), is emerging during treatment with immune checkpoint inhibitors (ICI). Our aim was to investigate the prevalence of such phenomenon and to assess its association with clinical variables and metabolic parameters by ¹⁸F-fludeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT). Methods: Data from 50 patients (34 male, 16 female, median age 73) with non-small cell lung carcinoma (NSCLC) and treated with ICI were prospectively collected. All patients underwent contrast-enhanced CT, ¹⁸F-FDG PET/CT, and complete peripheral blood sample at baseline before ICI. HPD was defined according to clinical and radiologic criteria. Because of the rapid disease progression or worsening of clinic conditions, radiologic response assessment was available for 46 patients. OS were analyzed using the Kaplan–Meier method and the log-rank test. A Cox proportional hazards regression analysis was used to evaluate factors independently associated with OS. Median follow-up was 12.4 months (9.7-15.2 months). Results: We identified the following response categories: 10 cases as complete/partial response (CR/PR), 17 cases with stable disease (SD), 5 patients with progressive disease (PD), and 14 with HPD. Among metabolic parameters we observed a statistically significant association between HPD status and tumor burden, expressed by both MTV (756.1ml for HPD vs 475.6ml for non-HPD, P = 0.011) and TLG (287.3 for HPD vs 62.1 for non-HPD, P = 0.042). Among clinical variables, 12/14 patients (85.7%) within the HPD group compared with 8/32 patients (25%) in the non-HDP group had more than two metastatic sites (p<0.001). In addition, the derived neutrophil-to-lymphocyte ratio (dNLR) and platelet counts was significantly associated with HPD status (P = 0.038, P = 0.025, respectively). Survival analysis showed a median OS of 4 months for HPD group compared with 15 months within non-HPD patients (P = 0.003). Likewise, median OS was significantly different when we considered all the response categories: CR/PR, SD, PD, and HPD (P = 0.001). Finally, Multivariate analysis identified MTV and dNLR as independent predictors for OS. Conclusion: Our results suggest that the use of ICI might represent a concern in patients with high metabolic tumor burden and inflammatory indexes at baseline. However Additional studies are needed.

Objectives: Radioactive iodine (¹³¹I) therapy may be used to treat thyroid cancer in end-stage renal disease patients who undergo hemodialysis. Because iodine predominantly utilizes renal clearance, treatment management in hemodialysis patients may be problematic, and no formal recommendations on hemodialysis currently exist. This work details our experience with treating thyroid cancer with iodine in chronic renal failure patients who require hemodialysis and details the therapeutic dosimetry results obtained during treatment to ensure that the dose to the bone marrow (BM) was acceptable. Methods: We treated 6 patients in the metabolic radiotherapy unit after thyroid stimulation. Two hemodialysis sessions in the metabolic radiotherapy unit were performed at 42 and 90 hours after radiopharmaceutical administration. BM toxicity was estimated with activity measurements from blood samples and with whole-body measurements that were regularly repeated during hospitalization and measured with a gamma counter. The patients underwent thyroid and hematologic monitoring to assess treatment efficacy and therapeutic toxicity in the short, medium and long term. Results: Whole-body activity was reduced on average by 66.7% [60.1-71.5] after the first dialysis session and by 53.3% [30.4-67.8] after the second. The mean estimated total absorbed dose to the BM was 0.992 Gy for all patients [0.431 – 2.323]. We did not observe any significant hematologic toxicity, and the clinical, biological and ultrasound test results confirmed the success of ablative treatment for the majority of patients. Conclusion: An approximately 30% reduction from the nominal dose in the amount of ¹³¹I activity for hemodialysis patients with thyroid cancer appears to strike an appropriate balance between the absence of BM toxicity and therapeutic efficacy. To avoid overirradiation, we recommend pretherapeutic dosimetry studies for metastatic patients to calculate the amount of activity to be administered as well as dosimetry monitoring during the hemodialysis sessions performed after therapeutic dose administration and under the same conditions.

Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for positron emission tomography (PET) or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in a number of malignancies including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce ⁸⁹Zr-radiolabeled onartuzumab (a monovalent, anti-human c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous ⁸⁹Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing ⁸⁹Zr-oxalate, the photoactive chelate DFO-aryl azide (DFO-ArN3) and MetMAb to give ⁸⁹ZrDFO-azepin-onartuzumab. As a control, ⁸⁹ZrDFO-Bn-NCS-onartuzumab was prepared via a conventional two-step process using pre-purified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0–72 h) was performed in female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image. Tumor specificity of ⁸⁹ZrDFO-azepin-onartuzumab was assessed by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced ⁸⁹ZrDFO-azepin-onartuzumab in <15 min. with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity (RCP) ~90% and a molar activity (Am) of ~1.5 MBq nmol^-1. Reaction optimization improved the radiochemical conversion (RCC) of ⁸⁹ZrDFO-azepin-onartuzumab to 56.9±4.1% (n = 3), with isolated RCYs of 41.2±10.6% (n = 3), and RCPs >90%. Conventional methods produced ⁸⁹ZrDFO-Bn-NCS-onartuzumab with isolated RCY >97%, RCP >97% and Am ~14.0 MBq nmol^-1. Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake reached 15.37±5.21 %ID g^-1, 6.56±4.03 %ID g^-1, respectively for ⁸⁹ZrDFO-azepin-onartuzumab (n = 4), and 21.38±11.57 %ID g^-1 and 18.84±6.03 %ID g^-1 for ⁸⁹ZrDFO-Bn-NCS-onartuzumab (n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g^-1) of ⁸⁹ZrDFO-azepin-onartuzumab (n = 4). Conclusion: Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing ⁸⁹Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.

Objective: To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using ¹⁸F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n = 19) underwent magnetic resonance magnetic and ¹⁸F-DPA-714 PET. A threshold of significant activation of ¹⁸F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.9±9.7%; WM in controls=14.0±7.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.1±13.5%, 45.0±17.9%, and 51.9±22.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, P = 0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, P = 0.009) and in T1-spin-echo lesions (OR=1.06, P = 0.036), were significantly associated with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. ¹⁸F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory.

Acidosis is a key driver for many diseases, including cancer, sepsis, and stroke. The spatiotemporal dynamics of dysregulated pH across disease remains elusive and current diagnostic strategies do not provide localization of pH alterations. We sought to explore if PET imaging using hydrophobic cyclic peptides that partition into the cellular membrane at low extracellular pH (denoted as "pHLIC") can permit accurate in vivo visualization of acidosis. Methods: Acid-sensitive cyclic peptide c[E4W5C] pHLIC was conjugated to bifunctional maleimide-NO2A and radiolabeled with copper-64 (t1/2 = 12.7 h). C57BL/6J mice were administered LPS (15 mg/kg) or saline (vehicle) and serially imaged with [⁶⁴Cu]Cu-c[E4W5C] over 24 h. Ex vivo autoradiography was performed on resected brain slices and subsequently stained with cresyl violet to enable high-resolution spatial analysis of tracer accumulation. A non- pH-sensitive cell-penetrating control peptide (c[R4W5C]) was used to confirm specificity of [⁶⁴Cu]Cu-c[E4W5C]. CD11b (macrophage/microglia) and TMEM119 (microglia) immunostaining was performed to correlate extent of neuroinflammation with [⁶⁴Cu]Cu-c[E4W5C] PET signal. Results: [⁶⁴Cu]Cu-c[E4W5C] radiochemical yield and purity was >95% and >99% respectively, with molar activity >0.925 MBq/nmol. Significantly increased [⁶⁴Cu]Cu-c[E4W5C] uptake was observed in LPS-treated mice (vs. vehicle) within peripheral tissues including blood, lungs, liver, and small intestines (P < 0.001-0.05). Additionally, there was significantly increased [⁶⁴Cu]Cu-c[E4W5C] uptake in the brains of LPS-treated animals. Autoradiography confirmed increased uptake in the cerebellum, cortex, hippocampus, striatum, and hypothalamus of LPS-treated mice (vs. vehicle). Immunohistochemical (IHC) analysis revealed microglial/macrophage infiltrate, suggesting activation in brain regions containing increased tracer uptake. [⁶⁴Cu]Cu-c[R4W5C] demonstrated significantly reduced uptake in the brain and periphery of LPS mice compared to the acid-mediated [⁶⁴Cu]Cu-c[E4W5C] tracer. Conclusion: Here, we demonstrate that a pH-sensitive PET tracer specifically detects acidosis in regions associated with sepsis-driven pro-inflammatory responses. This study suggests that [⁶⁴Cu]Cu-pHLIC is a valuable tool to noninvasively assess acidosis associated with both central and peripheral innate immune activation.

Rationale: The effects of tobacco smoking on the brain’s immune system are not well elucidated. While nicotine is immunosuppressive, other constituents in tobacco smoke have inflammatory effects. Positron Emission Tomography (PET) imaging of the 18-kDa translocator protein (TSPO) provide a biomarker for microglia, the brain’s primary immunocompetent cells. This work compared brain TSPO levels in 20 tobacco smokers (abstinent for at least 2 hours) and 20 nonsmokers using a fully quantitative modeling approach for the first time. Methods: [¹¹C]PBR28 PET scans were acquired with arterial blood sampling to estimate the metabolite-corrected input function. [¹¹C]PBR28 volumes of distribution (V_T) were estimated throughout the brain with multilinear analysis. Results: Statistical analyses revealed no evidence for significant differences in regional [¹¹C]PBR28 V_T between smokers and non-smokers (whole-brain Cohen’s d=0.09) despite adequate power to detect medium effect sizes. Conclusion: These findings inform previous PET studies reporting lower TSPO radiotracer concentrations in brain (measured as standardized uptake value, SUV) of tobacco smokers compared to nonsmokers by demonstrating the importance of accounting for radiotracer concentrations in plasma. These findings suggest that compared to nonsmokers, smokers have comparable TSPO levels in brain. Additional work with other biomarkers is needed to fully characterize effects of tobacco smoking on the brain’s immune system.

We aimed to evaluate the diagnostic performance of ¹⁸F-FDG PET/CT for the detection of post-transplantation lymphoproliferative disorder (PTLD) in a pediatric population and explore its feasibility during response assessment. Methods: This retrospective study included 28 pediatric transplant recipients who underwent a total of 32 ¹⁸F-FDG PET/CT scans due to clinical suspicion of PTLD within an 8-year period. Pathology reports and 2-year follow-up were used as reference standard. Twenty-one response assessment ¹⁸F-FDG PET/CT scans were re-evaluated according to the Lugano criteria. Results: The diagnosis of PTLD was established in 14 patients (49%). Sensitivity, specificity, positive predictive value, and negative predictive value of ¹⁸F-FDG PET/CT for the detection of PTLD in children with a clinical suspicion of this disease, was 50% (7/14), 100% (18/18), 100% (7/7), and 72% (18/25), respectively. False-negative results occurred in patients with PTLD in the Waldeyer’s ring, cervical lymph nodes or small bowel with either non-destructive or polymorphic PTLD. Two of 5 interim ¹⁸F-FDG PET/CT scans and 3 of 9 end-of-treatment ¹⁸F-FDG PET/CT scans were false-positive. Conclusion: ¹⁸F-FDG PET/CT had good specificity and positive predictive value but low to moderate sensitivity and negative predictive value for the detection of PTLD in a 28 pediatric patient cohort with a clinical suspicion of this disease. False-negative results were confirmed in the Waldeyer’s ring, cervical lymph nodes and small bowel with either non-destructive or polymorphic PTLD subtypes. ¹⁸F-FDG PET/CT appears to have a limited role in the response assessment setting of pediatric PTLD, given the observed high proportions of false-positives both at interim and end-of-treatment evaluations.

Targeting tumor-expressed receptors using selective molecules for diagnostic, therapeutic or both diagnostic and therapeutic (theragnostic) purposes is a promising approach in oncological applications. Such approaches have increased significantly over the past decade. Peptides such as gastrin-releasing peptide receptors (GRPR) targeting radiopharmaceuticals are small molecules with fast blood clearance and urinary excretion. They demonstrate good tissue diffusion, low immunogenicity, and highly selective binding to their target cell-surface receptors. They are also easily produced. GRPR, part of the bombesin (BBN) family, are overexpressed in many tumors, including breast and prostate cancer, and therefore represent an attractive target for future development.

Head motion degrades image quality and causes erroneous parameter estimates in tracer kinetic modeling in brain PET studies. Existing motion correction methods include frame-based image-registration (FIR) and correction using real-time hardware-based motion tracking (HMT) information. However, FIR cannot correct for motion within one predefined scan period while HMT is not readily available in the clinic since it typically requires attaching a tracking device to the patient. In this study, we propose a motion correction framework with a data-driven algorithm, i.e., using the PET raw data itself, to address these limitations. Methods: We propose a data-driven algorithm, Centroid of Distribution (COD), to detect head motion. In COD, the central coordinates of the line of response (LOR) of all events are averaged over 1-sec intervals to generate a COD trace. A point-to-point change in the COD trace in one direction that exceeded a user-defined threshold was defined as a time point of head motion, which was followed by manually adding additional motion time points. All the frames defined by such time points were reconstructed without attenuation correction and rigidly registered to a reference frame. The resulting transformation matrices were then used to perform the final motion compensated reconstruction. We applied the new COD framework to 23 human dynamic datasets, all containing large head motions, with ¹⁸F-FDG (N = 13) and ¹¹C-UCB-J (N = 10), and compared its performance with FIR and with HMT using the Vicra, which can be considered as the "gold standard". Results: The COD method yielded 1.0±3.2% (mean ± standard deviation across all subjects and 12 grey matter regions) SUV difference for ¹⁸F-FDG (3.7±5.4% for ¹¹C-UCB-J) compared to HMT while no motion correction (NMC) and FIR yielded -15.7±12.2% (-20.5±15.8%) and -4.7±6.9% (-6.2±11.0%), respectively. For ¹⁸F-FDG dynamic studies, COD yielded differences of 3.6±10.9% in Ki value as compared to HMT, while NMC and FIR yielded -18.0±39.2% and -2.6±19.8%, respectively. For ¹¹C-UCB-J, COD yielded 3.7±5.2% differences in VT compared to HMT, while NMC and FIR yielded -20.0±12.5% and -5.3±9.4%, respectively. Conclusion: The proposed COD-based data-driven motion correction method outperformed FIR and achieved comparable or even better performance as compared to the Vicra HMT method in both static and dynamic studies.

Respiratory gating is the standard to overcome respiration effects degrading image quality in positron emission tomography (PET). Data-driven gating (DDG) using signals derived from PET raw data are promising alternatives to gating approaches requiring additional hardware. However, continuous bed motion (CBM) scans require dedicated DDG approaches for axially-extended PET, compared to DDG for conventional step-and-shoot scans. In this study, a CBM-capable DDG algorithm was investigated in a clinical cohort, comparing it to hardware-based gating using gated and fully motion-corrected reconstructions. Methods: 56 patients with suspected malignancies in thorax or abdomen underwent whole-body ¹⁸F-FDG CBM-PET/CT imaging using DDG and hardware-based respiratory gating (pressure-sensitive belt gating, BG). Correlation analyses were performed on both gating signals. Besides static reconstructions, BG and DDG were used for optimally-gated PET (BG-OG, DDG-OG) and fully motion-corrected PET (elastic motion correction; BG-EMOCO, DDG-EMOCO). Metabolic volumes, SUV_max and SUVmean of lesions were compared amongst the reconstructions. Additionally, the quality of lesion delineation in different PET reconstructions was independently evaluated by three experts. Results: Global correlation coefficients between BG and DDG signals amounted to 0.48±0.11, peaking at 0.89±0.07 when scanning the kidney and liver region. In total, 196 lesions were analyzed. SUV measurements were significantly higher in BG-OG, DDG-OG, BG-EMOCO and DDG-EMOCO compared to static images (P<0.001; median SUV_max: static, 14.3±13.4; BG-EMOCO, 19.8±15.7; DDG-EMOCO, 20.5±15.6; BG-OG, 19.6±17.1; DDG-OG, 18.9±16.6). No significant differences between BG-OG and DDG-OG, and BG-EMOCO and DDG-EMOCO, respectively, were found. Visual lesion delineation was significantly better in BG-EMOCO and DDG-EMOCO than in static reconstructions (P<0.001); no significant difference was found comparing BG and DDG (EMOCO, OG, respectively). Conclusion: DDG-based motion-compensation of CBM-PET acquisitions outperforms static reconstructions, delivering qualities comparable to hardware-based approaches. The new algorithm may be a valuable alternative for CBM-PET systems.

Depth-encoding detectors with single-ended readout provide a practical, cost-effective approach for constructing high resolution and high sensitivity PET scanners. However, the current iteration of such detectors utilizes a uniform glass light guide to achieve depth-encoding, resulting in non-uniform performance throughout the detector array due to suboptimal intercrystal light sharing. We introduce Prism-PET, a single-ended readout PET detector module with a segmented light guide composed of an array of prismatoids that introduces enhanced, deterministic light sharing. Methods: High resolution PET detector modules were fabricated with single-ended readout of polished multicrystal lutetium yttrium orthosilicate (LYSO) scintillator arrays directly coupled 4-to-1 and 9-to-1 to arrays of 3.2 x 3.2 mm² silicon photomultiplier pixels. Each scintillator array was coupled at the non-readout side to a light guide (one 4-to-1 module with a uniform glass light guide, one 4-to-1 Prism-PET module and one 9-to-1 Prism-PET module) to introduce intercrystal light sharing, which closely mimics the behavior of dual-ended readout with the additional benefit of improved crystal identification. Flood histogram data was acquired using a 3 MBq Na-22 source to characterize crystal identification and energy resolution. Lead collimation was used to acquire data at specific depths to determine depth-of-interaction (DOI) resolution. Results: The flood histogram measurements showed excellent and uniform crystal separation throughout the Prism-PET modules while the uniform glass light guide module had performance degradation at the edges and corners. A DOI resolution of 5.0 mm full width at half maximum (FWHM) and energy resolution of 13% were obtained in the uniform glass light guide module. By comparison, the 4-to-1 coupled Prism-PET module achieved 2.5 mm FWHM DOI resolution and 9% energy resolution. Conclusion: PET scanners based on our Prism-PET modules with segmented prismatoid light guide arrays can achieve high and uniform spatial resolution (9-to-1 coupling with ~ 1 mm crystals), high sensitivity, good energy and timing resolutions (using polished crystals and after applying DOI-correction), and compact size (depth-encoding eliminates parallax error and permits smaller ring-diameter).

Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following ¹⁷⁷Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.

The kappa opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, ¹¹C-GR103545, for PET imaging of KOR in humans. Although ¹¹C-GR103545 showed high brain uptake, good binding specificity, and selectivity to KOR, it displayed slow kinetics and relatively large test-retest variability (TRV) of distribution volume (V_T) estimates (15%). Therefore we set out to develop two novel KOR agonist radiotracers, ¹¹C-EKAP and ¹¹C-FEKAP, and in nonhuman primates, both tracers exhibited faster kinetics and comparable binding parameters to ¹¹C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test-retest PET scans with both ¹¹C-EKAP and ¹¹C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were generated for 14 regions of interest. One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate V_T. Time-stability of V_T values and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the non-displaceable binding potential (BP_ND) for the three tracers (¹¹C-EKAP, ¹¹C-FEKAP and ¹¹C-GR103545), were compared using a graphical method. Results: For both tracers, regional TACs were fitted well with the 2TC model and MA1 method (t*=20min), but not with the 1TC model. Given unreliably estimated parameters in several fits with the 2TC model and a good match between V_T values from MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V_T values were highest for ¹¹C-GR103545, followed by ¹¹C-EKAP, then ¹¹C-FEKAP. Minimum scan time for stable V_T measurement was 90 and 110min for ¹¹C-EKAP and ¹¹C-FEKAP, respectively, compared with 140min for ¹¹C-GR103545. The mean absolute TRV in MA1 V_T estimates was 7% and 18% for ¹¹C-EKAP and ¹¹C-FEKAP, respectively. BP_ND levels were similar for ¹¹C-FEKAP and ¹¹C-GR103545, but ~25% lower for ¹¹C-EKAP. Conclusion: The two novel KOR agonist tracers showed faster tissue kinetics than ¹¹C-GR103545. Even with slightly lower BP_ND, ¹¹C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, based on the shorter minimum scan time and excellent test-retest.

We developed a first-of-kind dasatinib-derivative imaging agent, ¹⁸F-SKI-249380 (¹⁸F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using ¹⁸F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min post-injection of ¹⁸F-SKI (mean: 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of ¹⁸F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7–2.3) and tumor-to-blood ratios of 1.6 (range, 0.8–2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03–0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30–90 min post-injection. Blood radio-assay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time 1.31 ± 0.81 min, plasma 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time 285 ± 148.49 min, plasma 240 ± 84.85 min; n = 2) or a small rise to plateau (n = 2). Like dasatinib, ¹⁸F-SKI underwent extensive metabolism post-administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 (SD 0.0034) mSv/MBq. Conclusion: ¹⁸F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

We reviewed ¹¹¹In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time-points) were obtained after infusion of the ¹¹¹In-DOTA-BC8 (176-406 MBq) in 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in males), and two marrow sites (acetabulum and sacrum) and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 hours post-infusion and percent of administered activity was determined. Radiation absorbed doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (S.D.) of administered activity (52 patients), which cleared monoexponentially with biological half-time of 293 ± 157 hours (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biological half-time 271 ± 185 hours (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biological half-time of 243 ± 144 hours (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with half-times of 215 ± 107 hours (43 patients) or longer (5 patients). Whole-body retention half-times averaged 198 ± 75 hours. Splenic uptake was higher in the AML/MDS group when compared to the lymphoma group (p ≤ 0.05) and to the multiple myeloma group (p ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed between the three malignancy groups. Average calculated radiation absorbed doses per unit administered activity for a therapy infusions of ⁹⁰Y-DOTA-BC8 were for red marrow: 470 ± 260 cGy/MBq, liver 1100 ± 330 cGy/MBq, spleen 4120 ± 1950 cGy/MBq, total body 7520 ± 20 cGy/MBq, osteogenic cells 290 ± 200 cGy/MBq, and kidneys 240 ± 200 cGy/MBqR. Conclusion: ¹¹¹In-DOTA-BC8 had long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were calculated for spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake among leukemia/MDS group when compared to lymphoma and multiple myeloma groups.

Introduction: Neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic castration-resistant prostate cancer (mCRPC). We investigated the effect of circulating neuroendocrine biomarkers on the efficacy of PSMA-targeted radioligand therapy (RLT). Methods: Neuroendocrine biomarker profiles (progastrin-releasing peptide, neuron-specific enolase, and chromogranin-A) were analyzed in 50 patients commencing ¹⁷⁷Lu-PSMA-617 RLT. The primary endpoint was PSA response in relation to baseline neuroendocrine marker profiles. Additional endpoints included progression-free survival. Tumor uptake on post-therapeutic scans, a known predictive marker for response, was used as control-variable. Results: Neuroendocrine biomarker profiles were abnormal in the majority of patients. Neuroendocrine biomarker levels did not predict treatment failure or early progression (P ≥ 0.13). By contrast, intense PSMA-ligand uptake in metastases predicted both treatment response (P = 0.0030) and reduced risk of early progression (P = 0.0111). Conclusion: Neuroendocrine marker profiles do not predict adverse outcome of RLT. By contrast, high ligand uptake was confirmed to be crucial for achieving tumor-response.

Purpose: To determine the effect of smooth filter and partial volume correction (PVC) method on measured prostate-specific membrane antigen (PSMA) activity in small metastatic lesions and to determine the impact of these changes on the molecular imaging (mi) PSMA scoring. Materials & Methods: Men with biochemical recurrence of prostate cancer with negative CT and bone scintigraphy were referred for ¹⁸F-DCFPyL PET/CT. Examinations were performed on one of 2 PET/CT scanners (GE Discovery 610 or Siemens mCT40). All suspected tumor sites were manually contoured on co-registered CT and PET images, and each was assigned a miPSMA score as per the PROMISE criteria. The PVC factors were calculated for every lesion using the anatomical CT and then applied to the unsmoothed PET images. The miPSMA scores, with and without the corrections, were compared, and a simplified "rule of thumb" (RoT) correction factor (CF) was derived for lesions at various sizes (<4mm, 4-7mm, 7-9mm, 9-12mm). This was then applied to the original dataset and miPSMA scores obtained using the RoT CF were compared to those found using the actual corrections. Results: There were 75 men (median age, 69 years; median serum PSA of 3.69 ug/L) with 232 metastatic nodes < 12 mm in diameter (mean lesion volume of 313.5 ± 309.6 mm³). Mean SUV_max before and after correction was 11.0 ± 9.3 and 28.5 ± 22.8, respectively (p<0.00001). The mean CF for lesions <4mm (n = 22), 4-7mm (n = 140), 7-9mm (n = 50), 9-12 mm (n = 20) was 4 (range: 2.5-6.4), 2.8 (range: 1.6-4.9), 2.3 (range: 1.6-3.3) and 1.8 (range 1.4-2.4), respectively. Overall miPSMA scores were concordant between the corrected dataset and RoT in 205/232 lesions (88.4%). Conclusion: There is a significant effect of smooth filter and partial volume correction on measured PSMA activity in small nodal metastases, impacting the miPSMA score.

Objectives: The study compared the diagnostic performance of Planar Ventilation/perfusion (V/Q) and V/Q Single-photon computed tomography (SPECT), and determined whether combining perfusion scanning with low-dose computed tomography (Q-LDCT) may be equally effective in a prospective study of patients with chronic thromboembolic pulmonary hypertension (CTEPH) patients. Background: V/Q scanning is recommended for excluding CTEPH during the diagnosis of pulmonary hypertension (PH). However, Planar V/Q and V/Q SPECT techniques have yet to be compared in patients with CTEPH. Methods: Patients with suspected PH were eligible for the study. PH attributable to left heart disease or lung disease was excluded, and patients whose PH was confirmed by right heart catheterization and who completed Planar V/Q, V/Q-SPECT, Q-LDCT, and pulmonary angiography were included. V/Q images were interpreted and patients were diagnosed as instructed by the 2009 EANM guidelines, and pulmonary angiography analyses were used as a reference standard. Results: A total of 208 patients completed the study, including 69 with CTEPH confirmed by pulmonary angiography. Planar V/Q, V/Q-SPECT, and Q-LDCT were all highly effective for diagnosing CTEPH, with no significant differences in sensitivity or specificity observed among the three techniques (Planar V/Q [sensitivity/specificity]: 94.20%/92.81%; V/Q-SPECT: 97.10%/91.37%, Q-LCDT: 95.65%/90.65%). However, V/Q-SPECT was significantly more sensitive (V/Q-SPECT: 79.21%; Planar V/Q: 75.84%, P = 0.012; Q-LDCT: 74.91%, p<0.001), and Planar V/Q was significantly more specific (Planar V/Q: 54.14%; V/Q-SPECT 46.05%, p<0.001; Q-LDCT: 46.05%, P = 0.001) than the other two techniques for identifying perfusion defects in individual lung segments. Conclusion: Both Planar V/Q and V/Q-SPECT were highly effective for diagnosing CTEPH, and Q-LDCT may be a reliable alternative method for patients who are unsuitable for ventilation imaging.

Background: Patients with NHL who are treated with rituximab may develop resistant disease, often associated with changes in expression of CD20. The next generation β-particle emitting radioimmunoconjugate ¹⁷⁷Lu-lilotomab-satetraxetan (Betalutin®) was shown to up-regulate CD20 expression in different rituximab-sensitive NHL cell lines and to act synergistically with rituximab in a rituximab-sensitive NHL animal model. We hypothesized that ¹⁷⁷Lu-lilotomab-satetraxetan may be used to reverse rituximab-resistance in NHL. Methods: The rituximab-resistant Raji2R and the parental Raji cell lines were used. CD20 expression was measured by flow cytometry. ADCC was measured by a bioluminescence reporter assay. The efficacies of combined treatments with ¹⁷⁷Lu-lilotomab-satetraxetan (150MBq/kg or 350MBq/kg) and rituximab (4x10mg/kg) were compared with those of single agents or saline in a Raji2R-xenograft model. Cox-regression and the Bliss independence model were used to assess synergism. Results: Rituximab-binding in Raji2R cells was 36±5% of that in the rituximab-sensitive Raji cells. ¹⁷⁷Lu-lilotomab-satetraxetan treatment of Raji2R cells increased the binding to 53±3% of the parental cell line. Rituximab ADCC-induction in Raji2R cells was 20±2% of that induced in Raji cells, while treatment with ¹⁷⁷Lu-lilotomab-satetraxetan increased the ADCC-induction to 30±3% of the Raji cells, representing a 50% increase (p<0.05). The combination of rituximab with 350MBq/kg ¹⁷⁷Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1^nu mice. Conclusion: ¹⁷⁷Lu-lilotomab-satetraxetan has the potential to reverse rituximab-resistance; it increases binding and ADCC-activity in-vitro and can synergistically improve anti-tumor efficacy in-vivo.

Rationale: Neuroinflammation has been implicated in Amyotrophic Lateral Sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, some challenges have to be overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers (¹¹C-PBR28 and ¹⁸F-DPA714) is feasible, after validation of an established ¹¹C-PBR28 PET pseudoreference analysis technique for ¹⁸F-DPA714. Methods: 7 ALS-Belgium (58.9±6.7 years,5M) and 8 HV-Belgium (52.1±15.2 years,3M); and 7 ALS-US (53.4±9.8 years,5M) and 7 HV-US (54.6±9.6 years,4M) from a previously published study (1) underwent dynamic ¹⁸F-DPA714 (Leuven, Belgium) or ¹¹C-PBR28 (Boston, US) PET-MR scans. For ¹⁸F-DPA714, volume of distribution (VT) maps were compared to standardized uptake value ratios (SUVR)40-60 calculated using the pseudoreference regions (1)cerebellum, (2)occipital cortex, and (3)whole brain without ventricles (WB-ventricles). Also for ¹¹C-PBR28, SUVR60-90 using WB-ventricles were calculated. Results: In line with previous studies, increased ¹⁸F-DPA714 uptake (17.0±5.6%) in primary motor cortices was observed in ALS, as measured by both VT and SUVR40-60 approaches. Highest sensitivity was found for SUVRWB-ventricles (average cluster 21.6±0.1%). ¹⁸F-DPA714 VT ratio and SUVR40-60 results were highly correlated (r>0.8, p<0.001). A similar pattern of increased uptake (average cluster 20.5±0.5%) in primary motor cortices was observed in ALS with ¹¹C-PBR28 using the SUVRWB-ventricles. Analysis of the ¹⁸F-DPA714 and ¹¹C-PBR28 data together, resulted in a more extensive pattern of significant increased glial activation in the bilateral primary motor cortices. Conclusion: The same pseudoreference region analysis technique for ¹¹C-PBR28 PET imaging can be extended towards ¹⁸F-DPA714 PET. Therefore, in ALS, standardized analysis across these two tracers enables pooling of TSPO PET data across multiple centers and increase power of TSPO as biomarker for future therapeutic trials.

Cancer Survival is related to tumor volume. FDG PET measurement of tumor volume holds promise but is not yet a clinical tool. Measurements come in two forms: the total lesion volume (TLV) based on the number of voxels in the tumor and secondly the total lesion glycolysis (TLG) which is the TLV multiplied by the average SUL per voxel of the tumor (SUL is the standardize uptake value normalized for lean mass). In this study we measured tumor volume in patients with malignant pleural mesothelioma (MPM). METHODS: A threshold-based program in IDL was developed to measure tumor volume in FDG PET images. 19 patients with malignant pleural mesothelioma (MPM) were studied before and after two cycles (6 weeks) of chemo-immunotherapy. Measurements included the total lesion volume (TLV), Total Lesion Glycolysis (TLG), the sum of the SULs in the tumor (SUL- total), a measure of total FDG uptake, and the average SUL per voxel. RESULTS: Baseline MPM volumes (TLV) ranged from 11 to 2610 cc. TLG values ranged from 32 to 8552 SUL-cc and were strongly correlated with TLV. While tumor volumes ranged over 3 orders of magnitude, the average SUL per voxel, SUL-average, stayed within a narrow range of 2.4 to 5.3 units. Thus, TLV was the major component of TLG while SUL-average was a minor component and was essentially constant. Further evaluation of SUL-average showed that in this cohort it’s two components SUL-total and tumor volume changed in parallel and were strongly correlated, r= 0.99, p<.01. Thus, whether the tumors were large or small, the FDG uptake as measured by SUL-total was proportional to the total tumor volume. Conclusion: TLG equals TLV multiplied by the average SUL per voxel, essentially TLV multiplied by a constant. Thus TLG, commonly considered a measure of "metabolic activity" in tumors, is also in this cohort a measure of tumor volume. The constancy of SUL per voxel is due to FDG uptake being proportional to tumor volume. Thus, in this study, the FDG uptake was also a measure of volume.

Rationale: Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-N,N',N''-triacetic acid conjugated folate (¹⁸F-FOL) is a positron emission tomography (PET) tracer targeting folate receptor β (FR-β) that is expressed on activated macrophages at sites of inflammation. We evaluated ¹⁸F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied expression of FR-β in human cardiac sarcoidosis specimens. Methods: Myocarditis was induced by immunizing rats (n = 18) with porcine cardiac myosin in complete Freund’s adjuvant. Control rats (n = 6) were injected with Freund’s adjuvant alone. ¹⁸F-FOL was intravenously injected followed by imaging with a small animal PET/computed tomography (CT) scanner and autoradiography. Contrast-enhanced high-resolution CT or 2-deoxy-2-¹⁸F-fluoro-D-glucose (¹⁸F-FDG) PET images were used for co-registration. Rat tissue sections and myocardial autopsy samples of 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. Results: The myocardium of 10 out of 18 immunized rats showed focal macrophage-rich inflammatory lesions with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial ¹⁸F-FOL uptake co-localizing with inflammatory lesions (SUVmean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUVmean, 0.4 ± 0.2 and 0.4 ± 0.1, respectively; P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of ¹⁸F-FOL in myocardial inflammatory lesions. Uptake of ¹⁸F-FOL to inflamed myocardium was efficiently blocked by a non-labeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. Conclusion: In a rat model of autoimmune myocarditis, ¹⁸F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.

BiTE® (Bispecific T-cell engager) molecules are designed to engage and activate cytotoxic T-cells to kill tumor cells. Little is known about their biodistribution in immunocompetent settings. To explore their pharmacokinetics and the role of the immune cells, BiTE molecules were radiolabeled with positron emission tomography (PET) isotope zirconium-89 (89Zr) and studied in immunocompetent and immunodeficient mouse models. PET images and ex-vivo biodistribution in immunocompetent mice with 89Zr-muS110, targeting mouse CD3 (Kd = 2.9 nM) and mouse EpCAM (Kd = 21 nM), and 89Zr-hyS110, targeting only mouse CD3 (Kd = 2.9 nM), showed uptake in tumor, spleen and other lymphoid organs, while the human-specific control BiTE 89Zr-AMG 110 showed similar tumor uptake but lacked spleen uptake. 89Zr-muS110 spleen uptake was lower in immunodeficient than in immunocompetent mice. After repeated administration of non-radiolabeled muS110 to immunocompetent mice 89Zr-muS110 uptake in spleen, and other lymphoid tissues, decreased and was comparable to uptake in immunodeficient mice, indicating saturation of CD3 binding sites. Autoradiography and immunohistochemistry demonstrated colocalization of 89Zr-muS110 and 89Zr-hyS110 with CD3-positive T-cells in the tumor and spleen but not with EpCAM expression. Also, uptake in the duodenum correlated with a high incidence of T-cells. This study shows that in immunocompetent mice the BiTE 89Zr-muS110 distribution is predominantly based on its high affinity CD3 binding arm. Significance: 89Zr-muS110 biodistribution is mainly dependent on the T-cell targeting arm with limited contribution of its second arm, targeting EpCAM. These findings highlight the need for extensive biodistribution studies of novel bispecific constructs as results might have implications for their respective drug development and clinical translation.

McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3', 5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS, but not in humans with fibrous dysplasia. Positron emission tomography (PET) imaging of PDE4 with ¹¹C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods: ¹¹C-(R)-rolipram whole-body and brain PET scans were performed in six individuals with MAS (three for brain scans and six for whole-body scans) and nine healthy controls (seven for brain scans and six for whole-body scans). Results: ¹¹C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in ¹¹C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected, which could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with ¹¹C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.

Multidrug resistance-associated protein 1 (ABCC1) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. Aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-¹¹C-methylpurine (¹¹C-BMP), a prodrug radiotracer which is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-¹¹C-methylpurinyl))glutathione (¹¹C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571 and wild-type control rats underwent dynamic PET scans after administration of ¹¹C-BMP intravenously (i.v.) or by intratracheal aerosolization (i.t.). In vitro transport experiments were performed with unlabeled BMP in the human distal lung epithelial cell line NCI-H441. Results: Pulmonary kinetics of radioactivity were significantly different between wild-type and Abcc1(-/-) rats, but differences were more pronounced after i.t. than after i.v. administration. After i.v. administration lung exposure (AUClung) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower, whereas after i.t. administration AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after i.t. radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in presence than in absence of MK571. Conclusion: PET with pulmonary administered ¹¹C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms or concomitant drug intake on pulmonary ABCC1 activity.

Bone is the most common site of distant metastatic spread in prostate adenocarcinoma. Prostate-specific membrane antigen uptake has been described in both benign and malignant bone lesions, which can lead to false-positive findings on ⁶⁸Ga-prostate-specific membrane antigen-11 positron emission tomography (⁶⁸Ga-PSMA-11 PET). The purpose of this study was to evaluate the diagnostic accuracy of ⁶⁸Ga-PSMA-11 PET for osseous prostate cancer metastases and improve bone uptake interpretation using semi-quantitative metrics. METHODS: 56 prostate cancer patients (18 pre-prostatectomy, 38 biochemical recurrence) who underwent ⁶⁸Ga-PSMA-11 PET/MRI or PET/CT examinations with osseous PSMA-ligand uptake were included in the study. Medical records were reviewed retrospectively by board-certified nuclear radiologists to determine true or false positivity based on a composite endpoint. For each avid osseous lesion, biological volume, size, PSMA-RADS rating, maximum standardized uptake value (SUV_max), and ratio of lesion SUV_max to liver, blood pool, and background bone SUV_max were measured. Differences between benign and malignant lesions were evaluated for statistical significance, and cut-off values for these parameters were determined to maximize diagnostic accuracy. RESULTS: Among 56 participants, 13 patients (22.8%) had false-positive osseous ⁶⁸Ga-PSMA-11 findings and 43 patients (76.8%) had true-positive osseous ⁶⁸Ga-PSMA-11 findings. Twenty-two patients (39%) had 1 osseous lesion, 18 (32%) had 2-4 lesions, and 16 (29%) had 5 or more lesions. Cut-off values resulting in statistically significant (p<0.005) differences between benign and malignant lesions were: PSMA-RADS ≥4, SUV_max ≥4.1, SUV_max ratio of lesion to blood pool ≥2.11, to liver ≥0.55, and to bone ≥4.4. These measurements corresponded to lesion-based ⁶⁸Ga-PSMA-11 PET lesion detection rate for malignancy of 80%, 93%, 89%, 21%, 89%, and a specificity of 73%, 73%, 73%, 93%, 60%, respectively. CONCLUSION: PSMA-RADS rating, SUV_max, and SUV_max ratio of lesion to blood pool can help differentiate benign from malignant lesions on ⁶⁸Ga-PSMA-11 PET. SUV_max ratio to blood pool above 2.2 is a reasonable parameter to support image interpretation and presented superior lesion detection rate and specificity when compared to visual interpretation by PSMA RADS. These parameters hold clinical value by improving diagnostic accuracy for metastatic prostate cancer on ⁶⁸Ga-PSMA-11 PET/MRI and PET/CT.

Introduction: Gastrin Releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a ⁶⁸Ga-labelled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumours (‘MITIGATE’) (grant agreement number 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). Materials and Methods: The main objectives were evaluation of safety, biodistribution, dosimetry and preliminary tumor targeting of ⁶⁸Ga-NeoBOMB1 in patients with advanced TKI-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. ⁶⁸Ga-NeoBOMB1 was prepared using a kit procedure with a licensed ⁶⁸Ge/⁶⁸Ga generator. 3 MBq/kg body-weight were injected intravenously and safety parameters were assessed. PET/CT included dynamic imaging at 5 min, 11 min and 19 min as well as static imaging at 1, 2 and 3-4 h p.i. for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetics. Tumor targeting was assessed on a per-lesion and per-patient basis. Results: ⁶⁸Ga-NeoBOMB1 (50 µg) was prepared with high radiochemical purity (yield >97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 weeks. Dosimetry calculations revealed a mean adsorbed effective dose of 0.029 ± 0.06 mSv/MBq with highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7 ± 5.4% of injected dose 4h p.i.). Plasma metabolite analyses revealed high stability, metabolites were only detected in the urine. In three patients a significant uptake with increasing maximum standard uptake values (SUV_max at 2h p.i.: 4.3 to 25.9) over time was found in tumor lesions. Conclusion: This Phase I/IIa study provides safety data for ⁶⁸Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging and absorbed dose estimates are comparable to other ⁶⁸Ga-labelled radiopharmaceuticals used in clinical routine.

C-X-C chemokine receptor 4 is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. Magnetic resonance imaging (MRI) is the standard imaging technology for central nervous system involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. Methods: In this proof-of-concept study, 11 patients with lymphoma of the CNS (CNSL, n = 8 primary and n = 3 secondary involvement) were imaged with the CXCR4-directed positron emission tomography (PET) tracer ⁶⁸Ga-Pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by ⁶⁸Ga-Pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Results: ⁶⁸Ga-Pentixafor-PET showed excellent contrast characteristics to the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Conclusion: ⁶⁸Ga-Pentixafor-PET represents a novel diagnostic tool for central nervous system lymphoma with potential implications for theranostic approaches as well as response and risk assessment.

Fibroblast activation protein (FAP) has emerged as an interesting molecular target used in the imaging and therapy of various types of cancers. Gallium-68–labeled chelator-linked FAP inhibitors (FAPIs) have been successfully applied to positron emission tomography (PET) imaging of various tumor types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of an ¹⁸F–labeled glycosylated FAP inhibitor ([¹⁸F]FGlc-FAPI). Methods: An alkyne-bearing precursor was synthesized and subjected to click chemistry–based radiosynthesis of [¹⁸F]FGlc-FAPI by two-step ¹⁸F-fluoroglycosylation. FAP-expressing HT1080hFAP cells were used to study competitive binding to FAP, cellular uptake, internalization, and efflux of [¹⁸F]FGlc-FAPI in vitro. Biodistribution studies and in vivo small animal PET studies of [¹⁸F]FGlc-FAPI compared to [⁶⁸Ga]Ga-FAPI-04 were conducted in nude mice bearing HT1080hFAP tumors or U87MG xenografts. Results: [¹⁸F]FGlc-FAPI was synthesized with a 15% radioactivity yield and a high radiochemical purity of >99%. In HT1080hFAP cells, [¹⁸F]FGlc-FAPI showed specific uptake, a high internalized fraction, and low cellular efflux. Compared to FAPI-04 (IC50 = 32 nM), the glycoconjugate, FGlc-FAPI (IC50 = 167 nM), showed slightly lower affinity for FAP in vitro, while plasma protein binding was higher for [¹⁸F]FGlc-FAPI. Biodistribution studies revealed significant hepatobiliary excretion of [¹⁸F]FGlc-FAPI; however, small animal PET studies in HT1080hFAP xenografts showed higher specific tumor uptake of [¹⁸F]FGlc-FAPI (4.5 % injected dose per gram of tissue [ID/g]) compared to [⁶⁸Ga]Ga-FAPI-04 (2 %ID/g). In U87MG tumor–bearing mice, both tracers showed similar tumor uptake, but [¹⁸F]FGlc-FAPI showed a higher tumor retention. Interestingly, [¹⁸F]FGlc-FAPI demonstrated high specific uptake in bone structures and joints. Conclusion: [¹⁸F]FGlc-FAPI is an interesting candidate for translation to the clinic, taking advantage of the longer half-life and physical imaging properties of F-18. The availability of [¹⁸F]FGlc-FAPI may allow extended PET studies of FAP-related diseases, such as cancer, but also arthritis, heart diseases, or pulmonary fibrosis.

Purpose: We aimed to conduct a systematic review and meta-analysis of studies reporting the performance of radioactive iodine therapy (131-I therapy) in differentiating thyroid cancer (DTC) patients requiring a completion treatment following lobectomy. We also evaluated the response to 131-I therapy according to 2015ATA guidelines and the adverse events. Methods: A specific search strategy was designed to find articles evaluating the use of I-131 in patients with evidence of DTC after lobectomy. PubMed, CENTRAL, Scopus and Web of Science were searched. The search was updated until January 2020, without language restriction. Data were cross-checked and any discrepancy discussed. A proportion meta-analysis (with 95%CI) was performed using the random-effects model. Meta-regressions on I-131 success were attempted. Results: The pooled success ablation rate was 69% with better results in patients receiving a single administration of about 3.7 GBq; high heterogeneity was found (I2 85%), and publication bias was absent (Egger test: P = 0.57). Incomplete structural responses were recorded in only 14 of 695 (2%) patients enrolled in our analysis. Incomplete biochemical responses were observed in 8 to 24% of patients, with higher rates (24%) in patients receiving low radioiodine activities (~1.1 GBq) and lower rates (from 8 to 18%) in patients receiving higher activities of radioiodine (~3.7 Gbq). Neck pain due to thyroiditis was reported in up to 18% of patients but, in most cases, symptoms resolved after oral paracetamol or a short course of prednisone. Conclusion: Lobar ablation with 131-I is effective especially when high ¹³¹I activities are used. However, the rate of incomplete biochemical response to initial treatment appears to be slightly higher than the classical scheme of initial treatment of DTC. "Radioisotopic lobectomy" should be considered for patients with low-to-intermediate risk DTC requiring completion treatment after lobectomy due to specific individual risk factors and/or patient’s preferences.