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The differential diagnosis of a rapidly enlarging neck mass consists of many different benign ((haemorrhagic) cyst) and malignant (anaplastic thyroid cancer (ATC) and lymphoma) causes. ATC is a rare disease with a median survival of 6 months. As early diagnosis and management are key for fast-growing cancers, in our centre we have implemented a dedicated short-stay in-hospital fast-track diagnostic work-up for patients with a rapid growing mass in the neck. The goal of this track is to have a fast diagnostic and therapeutic plan for this disease. Based on three clinical cases we discuss our experience with this fast-track diagnostic work-up for rapidly growing mass in the neck and illustrate the additional value in this clinical entity.

Purpose: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [ 11 C]methionine PET/CT, [ 11 C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan., Methods: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99m Tc-sestamibi. All patients underwent [ 11 C]methionine PET/CT, [ 11 C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT., Results: A total of 32 patients were included in the study. With blinded evaluation, [ 11 C]choline PET/CT was positive in 28 patients (88%), [ 11 C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [ 11 C]choline PET/CT, [ 11 C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [ 11 C]choline PET/CT differed significantly from that of [ 11 C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively)., Conclusion: In the setting of pHPT with negative first-line imaging, [ 11 C]choline PET/CT is superior to [ 11 C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques., (© 2023. The Author(s).)

Background: In metastatic breast cancer (MBC), [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [ 18 F]FDG uptake in corresponding metastases., Patients and Methods: Patients with non-rapidly progressive MBC of all subtypes prospectively underwent a baseline histological metastasis biopsy and [ 18 F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [ 18 F]FDG uptake was expressed as maximum standardized uptake value (SUV max ) and results were expressed as geometric means., Results: Of 200 patients, 188 had evaluable metastasis biopsies, and 182 of these contained tumor. HER2 positivity and Ki-67 ≥ 20% were correlated with higher [ 18 F]FDG uptake (estimated geometric mean SUV max 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [ 18 F]FDG uptake was lowest in ER-positive/HER2-negative BC and highest in HER2-positive BC (geometric mean SUV max 6.8 and 10.0, respectively; p = 0.0058). Although [ 18 F]FDG uptake was lower in invasive lobular carcinoma ( n = 31) than invasive carcinoma NST ( n = 146) (estimated geometric mean SUV max 5.8 versus 7.8; p = 0.014), the metastasis detection rate was similar., Conclusions: [ 18 F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [ 18 F]FDG uptake, [ 18 F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332).

Efficacy of the human epidermal growth factor receptor (HER)2-targeting trastuzumab emtansine (T-DM1) in breast cancer (BC) relies on HER2 status determined by immunohistochemistry or fluorescence in-situ hybridization. Heterogeneity in HER2 expression, however, generates interest in "whole-body" assessment of HER2 status using molecular imaging. We evaluated the role of HER2-targeted molecular imaging in detecting HER2-positive BC lesions and patients unlikely to respond to T-DM1. Patients underwent zirconium-89 ( 89 Zr) trastuzumab (HER2) PET/CT and [ 18 F]-2-fluoro-2-deoxy-D-glucose (FDG) PET/CT before T-DM1 initiation. Based on 89 Zr-trastuzumab uptake, lesions were visually classified as HER2-positive (visible/high uptake) or HER2-negative (background/close to background activity). According to proportion of FDG-avid tumor load showing 89 Zr-trastuzumab uptake (entire/dominant part or minor/no part), patients were classified as HER2-positive and HER2-negative, respectively. Out of 265 measurable lesions, 93 (35%) were HER2-negative, distributed among 42 of the 90 included patients. Of these, 18 (19%) lesions belonging to 11 patients responded anatomically (>30% decrease in axial diameter from baseline) after three T-DM1 cycles, resulting in an 81% negative predictive value (NPV) of the HER2 PET/CT. In combination with early metabolic response assessment on FDG PET/CT performed before the second T-DM1 cycle, NPVs of 91% and 100% were reached in predicting lesion-based and patient-based (RECIST1.1) response, respectively. Therefore, HER2 PET/CT, alone or in combination with early FDG PET/CT, can successfully identify BC lesions and patients with a low probability of clinical benefit from T-DM1., (© 2024. The Author(s).)

Background: The use of computed tomography (CT) for attenuation correction (AC) in whole-body PET/CT can result in a significant contribution to radiation exposure. This can become a limiting factor for reducing considerably the overall radiation exposure of the patient when using the new long axial field of view (LAFOV) PET scanners. However, recent CT technology have introduced features such as the tin (Sn) filter, which can substantially reduce the CT radiation dose., Purpose: The purpose of this study was to investigate the ultra-low dose CT for attenuation correction using the Sn filter together with other dose reduction options such as tube current (mAs) reduction. We explore the impact of dose reduction in the context of AC-CT and how it affects PET image quality., Methods: The study evaluated a range of ultra-low dose CT protocols using five physical phantoms that represented a broad collection of tissue electron densities. A long axial field of view (LAFOV) PET/CT scanner was used to scan all phantoms, applying various CT dose reduction parameters such as reducing tube current (mAs), increasing the pitch value, and applying the Sn filter. The effective dose resulting from the CT scans was determined using the CTDI Vol reported by the scanner. Several voxel-based and volumes of interest (VOI)-based comparisons were performed to compare the ultra-low dose CT images, the generated attenuation maps, and corresponding PET images against those images acquired with the standard low dose CT protocol. Finally, two patient datasets were acquired using one of the suggested ultra-low dose CT settings., Results: By incorporating the Sn filter and adjusting mAs to the lowest available value, the radiation dose in CT images of PBU-60 phantom was significantly reduced; resulting in an effective dose of nearly 2% compared to the routine low dose CT protocols currently in clinical use. The assessment of PET images using VOI and voxel-based comparisons indicated relative differences (RD%) of under 6% for mean activity concentration (AC) in the torso phantom and patient dataset and under 8% for a source point in the CIRS phantom. The maximum RD% value of AC was 14% for the point source in the CIRS phantom. Increasing the tube current from 6 mAs to 30 mAs in patients with high BMI, or with arms down, can suppress the photon starvation artifact, whilst still preserving a dose reduction of 90%., Conclusions: Introducing a Sn filter in CT imaging lowers radiation dose by more than 90%. This reduction has minimal effect on PET image quantification at least for patients without Body Mass Index (BMI) higher than 30. Notably, this study results need validation using a larger clinical PET/CT dataset in the future, including patients with higher BMI., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

The purpose of this study was to quantify any differences between the SUVs of 89 Zr immuno-PET scans obtained using a PET/CT system with a long axial field of view (LAFOV; Biograph Vision Quadra) compared to a PET/CT system with a short axial field of view (SAFOV; Biograph Vision) and to evaluate how LAFOV PET scan duration affects image noise and SUV metrics. Methods: Five metastatic breast cancer patients were scanned consecutively on SAFOV and LAFOV PET/CT scanners. Four additional patients were scanned using only LAFOV PET/CT. Scans on both systems lasted approximately 30 min and were acquired 4 d after injection of 37 MBq of 89 Zr-trastuzumab. LAFOV list-mode data were reprocessed to obtain images acquired using shorter scan durations (15, 10, 7.5, 5, and 3 min). Volumes of interest were placed in healthy tissues, and tumors were segmented semiautomatically to compare coefficients of variation and to perform Bland-Altman analysis on SUV metrics (SUV max , SUV peak , and SUV mean ). Results: Using 30-min images, 2 commonly used lesion SUV metrics were higher for SAFOV than for LAFOV PET (SUV max , 16.2% ± 13.4%, and SUV peak , 10.1% ± 7.2%), whereas the SUV mean of healthy tissues showed minimal differences (0.7% ± 5.8%). Coefficients of variation in the liver derived from 30-min SAFOV PET were between those of 3- and 5-min LAFOV PET. The smallest SUV max and SUV peak differences between SAFOV and LAFOV were found for 3-min LAFOV PET. Conclusion: LAFOV 89 Zr immuno-PET showed a lower SUV max and SUV peak than SAFOV because of lower image noise. LAFOV PET scan duration may be reduced at the expense of increasing image noise and bias in SUV metrics. Nevertheless, SUV peak showed only minimal bias when reducing scan duration from 30 to 10 min., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

The latest technical development in the field of positron emission tomography/computed tomography (PET/CT) imaging has been the extension of the PET axial field-of-view. As a result of the increased number of detectors, the long axial field-of-view (LAFOV) PET systems are not only characterized by a larger anatomical coverage but also by a substantially improved sensitivity, compared with conventional short axial field-of-view PET systems. In clinical practice, this innovation has led to the following optimization: (1) improved overall image quality, (2) decreased duration of PET examinations, (3) decreased amount of radioactivity administered to the patient, or (4) a combination of any of the above. In this review, novel applications of LAFOV PET in oncology are highlighted and future directions are discussed.

Context: Imaging plays an important role in the characterization of adrenal tumors, but findings might be inconclusive. The clinical question is whether 18F fluodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is of diagnostic value in this setting., Objective: This meta-analysis was aimed at the diagnostic value of 18F-FDG PET/CT in differentiating benign from malignant adrenal tumors discovered either as adrenal incidentaloma or during staging or follow-up of oncologic patients., Data Sources: PubMed, EMBASE, Web of Science, and Cochrane Library were searched to select articles between 2000 and 2021., Study Selection: We included studies describing the diagnostic value of 18F-FDG PET/CT in adult patients with an adrenal tumor. Exclusion criteria were 10 or fewer participants, insufficient data on histopathology, clinical follow-up, or PET results. After screening of title and abstract by 2 independent reviewers, 79 studies were retrieved, of which 17 studies met the selection criteria., Data Extraction: Data extraction using a protocol and quality assessment according to QUADAS-2 was performed independently by at least 2 authors., Data Synthesis: A bivariate random-effects model was applied using R (version 3.6.2.). Pooled sensitivity and specificity of 18F-FDG PET/CT for identifying malignant adrenal tumors was 87.3% (95% CI, 82.5%-90.9%) and 84.7% (95% CI, 79.3%-88.9%), respectively. The pooled diagnostic odds ratio was 9.20 (95% CI, 5.27-16.08; P < .01). Major sources of heterogeneity (I2, 57.1% [95% CI, 27.5%-74.6%]) were in population characteristics, reference standard, and interpretation criteria of imaging results., Conclusions: 18F-FDG PET/CT had good diagnostic accuracy for characterization of adrenal tumors. The literature, however, is limited, in particular regarding adrenal incidentalomas. Large prospective studies in well-defined patient populations with application of validated cutoff values are needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Patient-tailored management of thyroid nodules requires improved risk of malignancy stratification by accurate preoperative nodule assessment, aiming to personalize decisions concerning diagnostics and treatment. Here, we perform an exploratory pilot study to identify possible patterns on multispectral optoacoustic tomography (MSOT) for thyroid malignancy stratification. For the first time, we directly correlate MSOT images with histopathology data on a detailed level., Methods: We use recently enhanced data processing and image reconstruction methods for MSOT to provide next-level image quality by means of improved spatial resolution and spectral contrast. We examine optoacoustic features in thyroid nodules associated with vascular patterns and correlate these directly with reference histopathology., Results: Our methods show the ability to resolve blood vessels with diameters of 250 μm at depths of up to 2 cm. The vessel diameters derived on MSOT showed an excellent correlation (R 2 -score of 0.9426) with the vessel diameters on histopathology. Subsequently, we identify features of malignancy observable in MSOT, such as intranodular microvascularity and extrathyroidal extension verified by histopathology. Despite these promising features in selected patients, we could not determine statistically relevant differences between benign and malignant thyroid nodules based on mean oxygen saturation in thyroid nodules. Thus, we illustrate general imaging artifacts of the whole field of optoacoustic imaging that reduce image fidelity and distort spectral contrast, which impedes quantification of chromophore presence based on mean concentrations., Conclusion: We recommend examining optoacoustic features in addition to chromophore quantification to rank malignancy risk. We present optoacoustic images of thyroid nodules with the highest spatial resolution and spectral contrast to date, directly correlated to histopathology, pushing the clinical translation of MSOT., (© 2023. The Author(s).)

Purpose: Monoclonal antibody (mAb)-based PET (immunoPET) imaging can characterise tumour lesions non-invasively. It may be a valuable tool to determine which patients may benefit from treatment with a specific monoclonal antibody (mAb) and evaluate treatment response. For 89 Zr immunoPET imaging, higher sensitivity of state-of-the art PET/CT systems equipped with silicon photomultiplier (SiPM)-based detector elements may be beneficial as the low positron abundance of 89 Zr causes a low signal-to-noise level. Moreover, the long physical half-life limits the amount of activity that can be administered to the patients leading to poor image quality even when using long scan durations. Here, we investigated the difference in semiquantitative performance between the PMT-based Biograph mCT, our clinical reference system, and the SiPM-based Biograph Vision PET/CT in 89 Zr immunoPET imaging. Furthermore, the effects of scan duration reduction using the Vision on semiquantitative imaging parameters and its influence on image quality assessment were evaluated., Methods: Data were acquired on day 4 post 37 MBq 89 Zr-labelled mAb injection. Five patients underwent a double scan protocol on both systems. Ten patients were scanned only on the Vision. For PET image reconstruction, three protocols were used, i.e. one camera-dependent protocol and European Association of Nuclear Medicine Research Limited (EARL) standards 1 and 2 compliant protocols. Vision data were acquired in listmode and were reprocessed to obtain images at shorter scan durations. Semiquantitative PET image parameters were derived from tumour lesions and healthy tissues to assess differences between systems and scan durations. Differently reconstructed images obtained using the Vision were visually scored regarding image quality by two nuclear medicine physicians., Results: When images were reconstructed using 100% acquisition time on both systems following EARL standard 1 compliant reconstruction protocols, results regarding semiquantification were comparable. For Vision data, reconstructed images that conform to EARL1 standards still resulted in comparable semiquantification at shorter scan durations (75% and 50%) regarding 100% acquisition time., Conclusion: Scan duration of 89 Zr immunoPET imaging using the Vision can be decreased up to 50% compared with using the mCT while maintaining image quality using the EARL1 compliant reconstruction protocol., (© 2023. The Author(s).)

Purpose: As novel tracers are continuously under development, it is important to obtain reliable radiation dose estimates to optimize the amount of activity that can be administered while keeping radiation burden within acceptable limits. Organ segmentation is required for quantification of specific uptake in organs of interest and whole-body dosimetry but is a time-consuming task which induces high interobserver variability. Therefore, we explored using manual segmentations versus an artificial intelligence (AI)-based automated segmentation tool as a pre-processing step for calculating whole-body effective doses to determine the influence of variability in volumetric whole-organ segmentations on dosimetry., Procedures: PET/CT data of six patients undergoing imaging with 89 Zr-labelled pembrolizumab were included. Manual organ segmentations were performed, using in-house developed software, and biodistribution information was obtained. Based on the activity biodistribution information, residence times were calculated. The residence times served as input for OLINDA/EXM version 1.0 (Vanderbilt University, 2003) to calculate the whole-body effective dose (mSv/MBq). Subsequently, organ segmentations were performed using RECOMIA, a cloud-based AI platform for nuclear medicine and radiology research. The workflow for calculating residence times and whole-body effective doses, as described above, was repeated., Results: Data were acquired on days 2, 4, and 7 post-injection, resulting in 18 scans. Overall analysis time per scan was approximately 4 h for manual segmentations compared to ≤ 30 min using AI-based segmentations. Median Jaccard similarity coefficients between manual and AI-based segmentations varied from 0.05 (range 0.00-0.14) for the pancreas to 0.78 (range 0.74-0.82) for the lungs. Whole-body effective doses differed minimally for the six patients with a median difference in received mSv/MBq of 0.52% (range 0.15-1.95%)., Conclusion: This pilot study suggests that whole-body dosimetry calculations can benefit from fast, automated AI-based whole organ segmentations., (© 2022. The Author(s).)

Purpose: Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC., Experimental Design: Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients., Results: The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53)., Conclusions: In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this., (©2022 The Authors; Published by the American Association for Cancer Research.)

This review describes the main benefits of using long axial field of view (LAFOV) PET in clinical applications. As LAFOV PET is the latest development in PET instrumentation, many studies are ongoing that explore the potentials of these systems, which are characterized by ultra-high sensitivity. This review not only provides an overview of the published clinical applications using LAFOV PET so far, but also provides insight in clinical applications that are currently under investigation. Apart from the straightforward reduction in acquisition times or administered amount of radiotracer, LAFOV PET also allows for other clinical applications that to date were mostly limited to research, e.g., dual tracer imaging, whole body dynamic PET imaging, omission of CT in serial PET acquisition for repeat imaging, and studying molecular interactions between organ systems. It is expected that this generation of PET systems will significantly advance the field of nuclear medicine and molecular imaging., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8 + T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8 + T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89 ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89 ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUV max ) 5.2, IQI 4.0-7.4). Higher SUV max was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8 + T cell distribution and pharmacodynamics within and between patients. In conclusion, 89 ZED88082A can characterize the complex dynamics of CD8 + T cells in the context of ICIs, and may inform immunotherapeutic treatments., (© 2022. The Author(s).)

Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The development of parathyroid-targeted treatment and imaging tracers could benefit from in vitro models. Therefore, we aim to establish a patient-derived parathyroid organoid model representing human parathyroid tissue. Hyperplastic parathyroid tissue was dispersed, and parathyroid organoids (PTOs) were cultured and characterized. PTO-derived cells exhibited self-renewal over several passages, indicative of the presence of putative stem cells. Immunofluorescence and RNA sequencing confirmed that PTOs phenocopy hyperplastic parathyroid tissue. Exposure of PTOs to increasing calcium concentrations and PTH-lowering drugs resulted in significantly reduced PTH excretion. PTOs showed specific binding of the imaging tracers 11 C-methionine and 99m Tc-sestamibi. These data show the functionality of PTOs resembling the parathyroid. This PTO model recapitulates the originating tissue on gene and protein expression and functionality, paving the way for future physiology studies and therapeutic target and tracer discovery., Competing Interests: Conflict of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Current European Association of Nuclear Medicine (EANM) Research Ltd. (EARL) guidelines for the standardisation of PET imaging developed for conventional systems have not yet been adjusted for long axial field-of-view (LAFOV) systems. In order to use the LAFOV Siemens Biograph Vision Quadra PET/CT (Siemens Healthineers, Knoxville, TN, USA) in multicentre research and harmonised clinical use, compliance to EARL specifications for 18 F-FDG tumour imaging was explored in the current study. Additional tests at various locations throughout the LAFOV and the use of shorter scan durations were included. Furthermore, clinical data were collected to further explore and validate the effects of reducing scan duration on semi-quantitative PET image biomarker accuracy and precision when using EARL-compliant reconstruction settings., Methods: EARL compliance phantom measurements were performed using the NEMA image quality phantom both in the centre and at various locations throughout the LAFOV. PET data (maximum ring difference (MRD) = 85) were reconstructed using various reconstruction parameters and reprocessed to obtain images at shorter scan durations. Maximum, mean and peak activity concentration recovery coefficients (RC) were obtained for each sphere and compared to EARL standards specifications. Additionally, PET data (MRD = 85) of 10 oncological patients were acquired and reconstructed using various reconstruction settings and reprocessed from 10 min listmode acquisition into shorter scan durations. Per dataset, SUVs were derived from tumour lesions and healthy tissues. ANOVA repeated measures were performed to explore differences in lesion SUV max and SUV peak . Wilcoxon signed-rank tests were performed to evaluate differences in background SUV peak and SUV mean between scan durations. The coefficient of variation (COV) was calculated to characterise noise., Results: Phantom measurements showed EARL compliance for all positions throughout the LAFOV for all scan durations. Regarding patient data, EARL-compliant images showed no clinically meaningful significant differences in lesion SUV max and SUV peak or background SUV mean and SUV peak between scan durations. Here, COV only varied slightly., Conclusion: Images obtained using the Vision Quadra PET/CT comply with EARL specifications. Scan duration and/or activity administration can be reduced up to a factor tenfold without the interference of increased noise., (© 2022. The Author(s).)

Background: Excellent performance characteristics of the Vision Quadra PET/CT, e.g. a substantial increase in sensitivity, allow for precise measurements of image-derived input functions (IDIF) and tissue time activity curves. Previously we have proposed a method for a reduced 30 min (as opposed to 60 min) whole body 18 F-FDG Patlak PET imaging procedure using a previously published population-averaged input function (PIF) scaled to IDIF values at 30-60 min post-injection (p.i.). The aim of the present study was to apply this method using the Vision Quadra PET/CT, including the use of a PIF to allow for shortened scan durations., Methods: Twelve patients with suspected lung malignancy were included and received a weight-based injection of 18 F-FDG. Patients underwent a 65-min dynamic PET acquisition which were reconstructed using European Association of Nuclear Medicine Research Ltd. (EARL) standards 2 reconstruction settings. A volume of interest (VOI) was placed in the ascending aorta (AA) to obtain the IDIF. An external PIF was scaled to IDIF values at 30-60, 40-60, and 50-60 min p.i., respectively, and parametric 18 F-FDG influx rate constant (K i ) images were generated using a t* of 30, 40 or 50 min, respectively. Herein, tumour lesions as well as healthy tissues, i.e. liver, muscle tissue, spleen and grey matter, were segmented., Results: Good agreement between the IDIF and corresponding PIF scaled to 30-60 min p.i. and 40-60 min p.i. was obtained with 7.38% deviation in K i . Bland-Altman plots showed excellent agreement in K i obtained using the PIF scaled to the IDIF at 30-60 min p.i. and at 40-60 min p.i. as all data points were within the limits of agreement (LOA) (- 0.004-0.002, bias: - 0.001); for the 50-60 min p.i. K i , all except one data point fell in between the LOA (- 0.021-0.012, bias: - 0.005)., Conclusions: Parametric whole body 18 F-FDG Patlak K i images can be generated non-invasively on a Vision Quadra PET/CT system. In addition, using a scaled PIF allows for a substantial (factor 2 to 3) reduction in scan time without substantial loss of accuracy (7.38% bias) and precision (image quality and noise interference)., (© 2022. The Author(s).)

Objective: Thyroglobulin (Tg) is an established tumor marker for differentiated thyroid carcinoma (DTC) patients. However, Tg immunoassays can be subject to Tg autoantibody (TgAb) interference resulting in incorrect Tg values. Therefore, Tg measurement with liquid chromatography-tandem mass spectrometry (LC-MS/MS) could be promising in patients with TgAbs. In this study, we compared Tg IRMA and Tg-LC-MS/MS analytically in the presence of TgAbs. Furthermore, we compared the clinical interpretation of results obtained by both Tg assays in DTC patients with lower TgAbs titers (<10 U/mL) during 131I ablation therapy., Methods: Totally 118 DTC patients diagnosed between 2006 and 2014 in a University Medical Center were followed with the Tg-IRMA (Thermo Fischer Scientific) and ARCHITECT anti-Tg (Abbott Laboratories) assays. We re-analyzed their samples with a sensitive Tg-LC-MS/MS method (Labcorp, limit of quantification of 0.02 ng/mL). Passing-Bablok regression analysis was performed on samples obtained during 131I ablation therapy and follow-up., Results: In 304 samples with lower TgAb titers, a good analytical agreement was found between both Tg assays (slope of 1.09 (95% CI: 1.05-1.16)). Fifty-five samples with potentially interfering TgAbs showed higher Tg-LC-MS/MS values than Tg-IRMA (slope of 1.45 (95% CI: 1.12->>100)). In patients(n = 91) with lower TgAb titers at the time of 131I ablation therapy, the Tg assays showed a clinical concordance of 91.2, 87.9, and 98.9%, respectively, using a Tg cut-off value of 1.0, 2.0, and 5.0 ng/mL., Conclusions: In DTC patients with lower titer TgAbs, Tg-IRMA is still a reliable and useful tumor marker. In DTC patients with potentially interfering TgAbs, Tg-IRMA values decreased due to TgAb interference.

In this PD-L1 ImagiNg to prediCt durvalumab treatment response in SCCHN (PINCH) study, we performed 89 Zr-DFO-durvalumab (anti-PD-L1 [programmed death ligand 1]) PET/CT in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) before monotherapy durvalumab treatment. The primary aims were to assess safety and feasibility of 89 Zr-DFO-durvalumab PET imaging and predict disease control rate during durvalumab treatment. Secondary aims were to correlate 89 Zr-DFO-durvalumab uptake to tumor PD-L1 expression, 18 F-FDG uptake, and treatment response of individual lesions. Methods: In this prospective multicenter phase I-II study (NCT03829007), patients with incurable R/M SCCHN underwent baseline 18 F-FDG PET and CT or MRI. Subsequently, PD-L1 PET imaging was performed 5 d after administration of 37 MBq of 89 Zr-DFO-durvalumab. To optimize imaging conditions, dose finding was performed in the first 14 patients. For all patients ( n = 33), durvalumab treatment (1,500 mg/4 wk, intravenously) was started within 1 wk after PD-L1 PET imaging and continued until disease progression or unacceptable toxicity (maximum, 24 mo). CT evaluation was assessed according to RECIST 1.1 every 8 wk. PD-L1 expression was determined by combined positive score on (archival) tumor tissue. 89 Zr-DFO-durvalumab uptake was measured in 18 F-FDG-positive lesions, primary and secondary lymphoid organs, and blood pool. Results: In total, 33 patients with locoregional recurrent ( n = 12) or metastatic SCCHN ( n = 21) were enrolled. 89 Zr-DFO-durvalumab injection was safe. A dose of 10 mg of durvalumab resulted in highest tumor-to-blood ratios. After a median follow-up of 12.6 mo, overall response rate was 26%. The disease control rate at 16 wk was 48%, with a mean duration of 7.8 mo (range, 1.7-21.1). On a patient level, 89 Zr-DFO-durvalumab SUV peak or tumor-to-blood ratio could not predict treatment response (hazard ratio, 1.5 [95% CI, 0.5-3.9; P = 0.45] and 1.3 [95% CI, 0.5-3.3; P = 0.60], respectively). Also, on a lesion level, 89 Zr-DFO-durvalumab SUV peak showed no substantial correlation to treatment response (Spearman ρ, 0.45; P = 0.051). Lesional 89 Zr-DFO-durvalumab uptake did not correlate to PD-L1 combined positive score but did correlate to 18 F-FDG SUV peak (Spearman ρ, 0.391; P = 0.005). Conclusion: PINCH is the first, to our knowledge, PD-L1 PET/CT study in patients with R/M SCCHN and has shown the feasibility and safety of 89 Zr-DFO-durvalumab PET/CT in a multicenter trial. 89 Zr-DFO-durvalumab uptake did not correlate to durvalumab treatment response., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding., Methods: This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e' mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers., Results: Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8-60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2-48.8). Between the first and second evaluation, the e' mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e' mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e' mean (β coefficient: -0.169, 95% CI: -0.292; -0.047, P = 0.008 and β coefficient: -0.177, 95% CI: -0.240; -0.113, P < 0.001, respectively)., Conclusions and Relevance: In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Background: Machine learning studies require a large number of images often obtained on different PET scanners. When merging these images, the use of harmonized images following EARL-standards is essential. However, when including retrospective images, EARL accreditation might not have been in place. The aim of this study was to develop a convolutional neural network (CNN) that can identify retrospectively if an image is EARL compliant and if it is meeting older or newer EARL-standards., Materials and Methods: 96 PET images acquired on three PET/CT systems were included in the study. All images were reconstructed with the locally clinically preferred, EARL1, and EARL2 compliant reconstruction protocols. After image pre-processing, one CNN was trained to separate clinical and EARL compliant reconstructions. A second CNN was optimized to identify EARL1 and EARL2 compliant images. The accuracy of both CNNs was assessed using fivefold cross-validation. The CNNs were validated on 24 images acquired on a PET scanner not included in the training data. To assess the impact of image noise on the CNN decision, the 24 images were reconstructed with different scan durations., Results: In the cross-validation, the first CNN classified all images correctly. When identifying EARL1 and EARL2 compliant images, the second CNN identified 100% EARL1 compliant and 85% EARL2 compliant images correctly. The accuracy in the independent dataset was comparable to the cross-validation accuracy. The scan duration had almost no impact on the results., Conclusion: The two CNNs trained in this study can be used to retrospectively include images in a multi-center setting by, e.g., adding additional smoothing. This method is especially important for machine learning studies where the harmonization of images from different PET systems is essential., (© 2022. The Author(s).)

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic., Competing Interests: Competing interests: EDV reports an advisory role at Daiichi Sankyo, NSABP, and Sanofi and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, Crescendo, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon (paid to UMCG). AvdW reports an advisory role at Janssen, Takeda, and Boehringer-Ingelheim (paid to UMCG) and research funding from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, and Takeda. ML-dH reports research funding from Merck, Bayer, and Amgen (paid to UMCG). SO reports research funding from Novartis, Pfizer and Celldex Therapeutics (paid to UMCG) and an advisory role at Bristol Myers Squibb (paid to the UMCG)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In treatment of neuroendocrine neoplasms (NENs), confirmation of somatostatin receptor expression with 68 Ga-DOTA somatostatin analogues is mandatory to determine eligibility for peptide receptor radionuclide therapy (PRRT). [ 18 F]DOPA can detect additional lesions compared to [ 68 Ga]DOTA-TOC. The aim of this study was to explore differences in tumour detection of both tracers and their relevance for selecting patients for PRRT. We retrospectively studied eight patients with NENs who underwent both [ 68 Ga]DOTA-TOC and carbidopa-enhanced [ 18 F]DOPA PET/CT, before first-time PRRT with [ 177 Lu]DOTA-TATE. Tracer order was influenced due to stock availability or to detect suspected metastases with a second tracer. On CT, disease control was defined as a lesion showing complete response, partial response, or stable disease, according to RECIST 1.1., Results: Seven patients with in total 89 lesions completed four infusions of 7.4 GBq [ 177 Lu]DOTA-TATE, one patient received only two cycles. Before treatment, [ 18 F]DOPA PET/CT detected significantly more lesions than [ 68 Ga]DOTA-TOC PET/CT (79 vs. 62, p < .001). After treatment, no difference in number of lesions with disease control was found for [ 18 F]DOPA-only (5/27) and [ 68 Ga]DOTA-TOC-only lesions (4/10, p = .25). [ 18 F]DOPA detected more liver metastases (24/27) compared to [ 68 Ga]DOTA-TOC (7/10, p = .006). Six patients showed inpatient heterogeneity in treatment response between [ 18 F]DOPA-only and [ 68 Ga]DOTA-TOC-only lesions., Conclusions: Response to PRRT with [ 177 Lu]DOTA-TATE was comparable for both [ 68 Ga]DOTA-TOC- and [ 18 F]DOPA-only NEN lesions. [ 18 F]DOPA may be capable of predicting response to PRRT while finding more lesions compared to [ 68 Ga]DOTA-TOC, although these additional lesions are often small of size and undetected by diagnostic CT., (© 2022. The Author(s).)

Purpose: To assess the impact of an [ 18 F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology., Methods: In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [ 18 F]FDG-PET/CT and were randomised to an [ 18 F]FDG-PET/CT-driven or diagnostic surgery group. In the [ 18 F]FDG-PET/CT-driven group, management was based on the [ 18 F]FDG-PET/CT result: when the index nodule was visually [ 18 F]FDG-positive, diagnostic surgery was advised; when [ 18 F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules., Results: Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [ 18 F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [ 18 F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2-40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [ 18 F]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively., Conclusion: An [ 18 F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules., Trial Registration Number: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544 ., (© 2021. The Author(s).)

Importance: Primary hyperparathyroidism (pHPT) is a common endocrine disorder with many diagnostic and treatment challenges. Despite high-quality guidelines, care is variable, and there is low adherence to evidence-based treatment pathways., Objective: To develop quality indicators (QIs) to evaluate the diagnosis and treatment of pHPT that could measure, improve, and optimize quality of care and outcomes for patients with this disease., Design, Setting, and Participants: This quality improvement study used a guideline-based approach to develop QIs that were ranked by a Canadian 9-member expert panel of 3 endocrinologists, 3 otolaryngologists, and 3 endocrine surgeons. Data were analyzed between September 2020 and May 2021., Main Outcomes and Measures: Candidate indicators (CIs) were extracted from published primary hyperparathyroidism guidelines and summarized with supporting evidence. The 9-member expert panel rated each CI on the validity, reliability, and feasibility of measurement. Final QIs were selected from CIs using the modified RAND-University of California, Los Angeles appropriateness methodology. All panelists were then asked to rank the top 5 QIs for primary, endocrine, and surgical care., Results: Forty QIs were identified and evaluated by the expert panel. After 2 rounds of evaluations and discussion, a total of 18 QIs were selected as appropriate measures of high-quality care. The top 5 QIs for primary, endocrine, and surgical care were selected following panelist rankings., Conclusions and Relevance: This quality improvement study proposes 18 QIs for the diagnosis and management of pHPT. Furthermore, the top 5 QIs applicable to physicians commonly treating pHPT, including general physicians, internists, endocrinologists, otolaryngologists, and surgeons, are included. These QIs not only assess the quality of care to guide the process of improvement, but also can assess the implementation of evidence-based guideline recommendations. Using these indicators in clinical practice and health system registries can improve quality and cost-effectiveness of care for patients with pHPT.

Context: No consensus exists about the optimal duration of the low-iodine diet (LID) in the preparation of 131I therapy in differentiated thyroid cancer (DTC) patients., Objective: This work aimed to investigate if a LID of 4 days is enough to achieve adequate iodine depletion in preparation for 131I therapy. In addition, the nutritional status of the LID was evaluated., Methods: In this prospective study, 65 DTC patients treated at 2 university medical centers were included between 2018 and 2021. The patients collected 24-hour urine on days 4 and 7 of the LID and kept a food diary before and during the LID. The primary outcome was the difference between the 24-hour urinary iodine excretion (UIE) on both days., Results: The median 24-hour UIE on days 4 and 7 of the LID were not significantly different (36.1 mcg [interquartile range, 25.4-51.2 mcg] and 36.5 mcg [interquartile range, 23.9-47.7 mcg], respectively, P = .43). On day 4 of the LID, 72.1% of the DTC patients were adequately prepared (24-hour UIE < 50 mcg), and 82.0% of the DTC patients on day 7 (P = .18). Compared to the self-reported regular diet, DTC patients showed a significantly (P < .01) lower percentage of nutrient intake (calories, protein, calcium, iodine, and water) during the LID., Conclusion: The 24-hour UIE on day 4 of the LID did not differ from day 7, and therefore shortening the LID from 7 to 4 days seems justified to prepare DTC patients for 131I therapy in areas with sufficient iodine intake and may be beneficial to maintain a sufficient nutritional intake during DTC treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: This study aims to generate a reproducible and generalizable Workflow model of ICG-angiography integrating Standardization and Quantification (WISQ) that can be applied uniformly within the surgical innovation realm independent of the user., Summary Background Data: Tissue perfusion based on indocyanine green (ICG)-angiography is a rapidly growing application in surgical innovation. Interpretation of results has been subjective and error-prone due to the lack of a standardized and quantitative ICG-workflow and analytical methodology. There is a clinical need for a more generic, reproducible, and quantitative ICG perfusion model for objective assessment of tissue perfusion., Methods: In this multicenter, proof-of-concept study, we present a generic and reproducible ICG-workflow integrating standardization and quantification for perfusion assessment. To evaluate our model's clinical feasibility and reproducibility, we assessed the viability of parathyroid glands after performing thyroidectomy. Biochemical hypoparathyroidism was used as the postoperative endpoint and its correlation with ICG quantification intraoperatively. Parathyroid gland is an ideal model as parathyroid function post-surgery is only affected by perfusion., Results: We show that visual subjective interpretation of ICG-angiography by experienced surgeons on parathyroid perfusion cannot reliably predict organ function impairment postoperatively, emphasizing the importance of an ICG quantification model. WISQ was able to standardize and quantify ICG-angiography and provided a robust and reproducible perfusion curve analysis. A low ingress slope of the perfusion curve combined with a compromised egress slope was indicative for parathyroid organ dysfunction in 100% of the cases., Conclusion: WISQ needs prospective validation in larger series and may eventually support clinical decision-making to predict and prevent postoperative organ function impairment in a large and varied surgical population., Competing Interests: The authors have no related personal conflicts of interest to declare that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grant from any funding agency in the public or commercial sector. The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [β-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers β-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Purpose: CX-072, a PD-L1-targeting Probody therapeutic, is engineered to be activated by tumor proteases that remove a masking peptide. To study effects on biodistribution and pharmacokinetics, we performed 89Zr-CX-072 positron emission tomography (PET) imaging., Experimental Design: Patients received ∼1 mg, 37 MBq 89Zr-CX-072 plus 0, 4, or 9 mg unlabeled CX-072 and PET scans at days 2, 4, and 7. After that, treatment comprised 10 mg/kg CX-072 q2 weeks (n = 7) + 3 mg/kg ipilimumab q3w 4× (n = 1). Normal organ tracer uptake was expressed as standardized uptake value (SUV)mean and tumor uptake as SUVmax. PD-L1 expression was measured immunohistochemically in archival tumor tissue., Results: Three of the eight patients included received 10-mg protein dose resulting in a blood pool mean SUVmean ± SD of 4.27 ± 0.45 on day 4, indicating sufficient available tracer. Tumor uptake was highest at day 7, with a geometric mean SUVmax 5.89 (n = 113) and present in all patients. The median follow-up was 12 weeks (4-76+). One patient experienced stable disease and two patients a partial response. PD-L1 tumor expression was 90% in one patient and ≤1% in the other patients. Mean SUVmean ± SD day 4 at 10 mg in the spleen was 8.56 ± 1.04, bone marrow 2.21 ± 0.46, and liver 4.97 ± 0.97. Four patients out of seven showed uptake in normal lymph nodes and Waldeyer's ring. The tracer was intact in the serum or plasma., Conclusions: 89Zr-CX-072 showed tumor uptake, even in lesions with ≤1% PD-L1 expression, and modest uptake in normal lymphoid organs, with no unexpected uptake in other healthy tissues., (©2021 American Association for Cancer Research.)

Background: 6-[ 18 F]fluoro-L-3,4-dihydroxyphenyl alanine ([ 18 F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [ 18 F]FDOPA is decarboxylated to [ 18 F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [ 18 F]FDOPA has been developed, [ 18 F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([ 18 F]FDOPA-L)., Aims: This study aimed to investigate whether the difference in molar activity affects the [ 18 F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [ 18 F]FDOPA-H would be equal to or higher than [ 18 F]FDOPA-L., Methods: We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [ 18 F]FDOPA-H and [ 18 F]FDOPA-L within a time span of 5 years. A total of 98 [ 18 F]FDOPA scans (49 [ 18 F]FDOPA-L and 49 [ 18 F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1-2 lesions) and higher tumor load (3-10 lesions)., Results: Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [ 18 F]FDOPA-H compared to [ 18 F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [ 18 F]FDOPA-H group with 3-10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L., Conclusion: [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV's, with slight increases in uptake of [ 18 F]FDOPA-H in comparison to [ 18 F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [ 18 F]FDOPA., (© 2021. The Author(s).)

Background: A diagnostic I-131 (Dx) scan is used to detect a thyroid remnant or metastases before treatment of differentiated thyroid cancer (DTC) with I-131. The aim of this study is to specify in which patients with DTC a Dx scan could have an additional value, by studying the effect of the Dx scan on clinical management., Methods: Patients with DTC, treated with I-131 after thyroidectomy were included in this retrospective cohort study. Twenty-four hours after administration of 37 MBq I-131 a whole body Dx scan and an uptake measurement at the original thyroid bed were performed. Outcomes of the Dx scan and the subsequent changes in clinical management, defined as additional surgery or adjustment of I-131 activity, were reported. Risk factors for a change in clinical management were identified with a binary logistic regression., Results: In 11 (4.2%) patients clinical management was changed, including additional surgery (n=5), lowering I-131 activity (n=5) or both (n=1). Risk factors for a change in clinical management were previous neck surgery (OR 5.9, 95% CI: 1.4-24.5), surgery in a non-tertiary center (OR 13.4, 95% CI: 2.8 - 63.8), TSH <53.4 mU/L (OR 19.64, 95% CI: 4.94-78.13), thyroglobulin ≥50.0 ng/L (OR 7.4, 95% CI: 1.6-34.9) and free T4 ≥4.75 pmol/L (OR 156.8, 95% CI: 128.4-864.2)., Conclusion: The Dx scan can potentially change clinical management before treatment with I-131, but the yield is low. A Dx-scan should only be considered for patients with a high pre-scan risk of a change in management, based on patient history and prior center-based surgical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van der Boom, Zandee, Dekkers, van der Horst-Schrivers, Jansen, Kruijff, Brouwers and Links.)

Purpose: Metabolically active tumour volume (MATV) is a potential quantitative positron emission tomography (PET) imaging biomarker in melanoma. Accumulating data indicate that low MATV may predict increased chance of response to immunotherapy and overall survival. However, metastatic melanoma can present with numerous (small) tumour lesions, making manual tumour segmentation time-consuming. The aim of this study was to evaluate multiple semi-automatic segmentation workflows to determine reliability and reproducibility of MATV measurements in patients with metastatic melanoma., Methods: An existing cohort of 64 adult patients with histologically proven metastatic melanoma was used in this study. 18 F-FDG PET/CT diagnostic baseline images were acquired using a European Association of Nuclear Medicine (EANM) Research Limited-accredited Siemens Biograph mCT PET/CT system (Siemens Healthineers, Knoxville, USA). PET data were analysed using manual, gradient-based segmentation and five different semi-automatic methods: three direct PET image-derived delineations (41MAX, A50P and SUV40) and two based on a majority-vote approach (MV2 and MV3), without and with (suffix '+') manual lesion addition. Correlation between the different segmentation methods and their respective associations with overall survival was assessed., Results: Correlation between the MATVs derived by the manual segmentation and semi-automated tumour segmentations ranged from R 2  = 0.41 for A50P to R 2  = 0.85 for SUV40+ and MV2+, respectively. Manual MATV segmentation did not differ significantly from the semi-automatic methods SUV40 (∆MATV mean ± SD 0.08 ± 0.60 mL, P = 0.303), SUV40+ (∆MATV - 0.10 ± 0.51 mL, P = 0.126), MV2+ (∆MATV - 0.09 ± 0.62 mL, P = 0.252) and MV3+ (∆MATV - 0.03 ± 0.55 mL, P = 0.615). Log-rank tests showed statistically significant overall survival differences between above and below median MATV patients for all segmentation methods with areas under the ROC curves of 0.806 for manual segmentation and between 0.756 [41MAX] and 0.807 [MV3+] for semi-automatic segmentations., Conclusions: Simple and fast semi-automated FDG PET segmentation workflows yield accurate and reproducible MATV measurements that correlate well with manual segmentation in metastatic melanoma. The most readily applicable and user-friendly SUV40 method allows feasible MATV measurement in prospective multicentre studies required for validation of this potential PET imaging biomarker for clinical use.

Purpose: The aim of this study was to retrospectively compare 18F-FDOPA versus 68Ga-DOTATOC PET in lesion detection rates and laboratory tumor markers in patients with neuroendocrine neoplasms (NENs)., Patients and Methods: All patients with histologically proven NEN between May 2015 and February 2019 were included who underwent both 18F-DOPA and 68Ga-DOTATOC PET scans within 6 months from each other (mean, 75; median, 38; range, 2-168 days). All patients, except those with pancreatic NEN, received carbidopa before 18F-DOPA PET. Based on the number of lesions on both modalities, patients were divided into 3 categories: more lesions on 18F-DOPA (DOPA > DOTA), more lesions on 68Ga-DOTATOC (DOTA > DOPA), and equal number of lesions (DOPA = DOTA). Tumor markers chromogranin A, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) within a maximum of 3 months around either scan were retrieved from the patients' charts., Results: 18F-DOPA revealed significantly more lesions compared with 68Ga-DOTATOC (611 vs 385, P < 0.05). Twenty-four patients were included in the DOPA > DOTA group with 16 small intestinal (SI) NENs, 3 large intestinal, 4 pancreatic, and 1 tumor of unknown origin (TUO). For the 9 patients in the DOTA > DOPA group, 4 were SI, 2 pancreatic, 1 lung, and 2 TUOs. Twelve patients in the DOPA = DOTA group had 6 pancreatic tumors, 3 SI, 1 ovarian, and 2 TUOs. Only serotonin and 5-HIAA showed significant higher values for DOPA > DOTA compared with DOTA > DOPA (mean 24 vs 4, P < 0.05, and 320 vs 81, P < 0.05, respectively). Cutoff values of 20 nmol/109 for serotonin, 185 μg/L for chromogranin A, and 200 nmol/L for 5-HIAA were found to include almost exclusively DOPA > DOTA patients., Conclusions: There is an advantage of carbidopa pretreated 18F-DOPA over 68Ga-DOTATOC PET, especially for large intestinal NENs with high levels of biomarkers. There seems to be a relationship between increased biomarker value and improved lesion detection rates with the 18F-DOPA PET scan, which requires further prospective analysis., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Whole-body Patlak images can be obtained from an acquisition of first 6 min of dynamic imaging over the heart to obtain the arterial input function (IF), followed by multiple whole-body sweeps up to 60 min pi. The use of a population-averaged IF (PIF) could exclude the first dynamic scan and minimize whole-body sweeps to 30-60 min pi. Here, the effects of (incorrect) PIFs on the accuracy of the proposed Patlak method were assessed. In addition, the extent of mitigating these biases through rescaling of the PIF to image-derived IF values at 30-60 min pi was evaluated., Methods: Using a representative IF and rate constants from the literature, various tumour time-activity curves (TACs) were simulated. Variations included multiplication of the IF with a positive and negative gradual linear bias over 60 min of 5, 10, 15, 20, and 25% (generating TACs using an IF different from the PIF); use of rate constants (K 1 , k 3 , and both K 1 and k 2 ) multiplied by 2, 1.5, and 0.75; and addition of noise (μ = 0 and σ = 5, 10 and 15%). Subsequent Patlak analysis using the original IF (representing the PIF) was used to obtain the influx constant (K i ) for the differently simulated TACs. Next, the PIF was scaled towards the (simulated) IF value using the 30-60-min pi time interval, simulating scaling of the PIF to image-derived values. Influence of variabilities in IF and rate constants, and rescaling the PIF on bias in K i was evaluated., Results: Percentage bias in K i observed using simulated modified IFs varied from - 16 to 16% depending on the simulated amplitude and direction of the IF modifications. Subsequent scaling of the PIF reduced these K i biases in most cases (287 out of 290) to < 5%., Conclusions: Simulations suggest that scaling of a (possibly incorrect) PIF to IF values seen in whole-body dynamic imaging from 30 to 60 min pi can provide accurate Ki estimates. Consequently, dynamic Patlak imaging protocols may be performed for 30-60 min pi making whole-body Patlak imaging clinically feasible.

It is unknown whether assessment of potential bone lesions in metastatic breast cancer (MBC) by 18 F-FDG PET instead of 99m Tc bone scintigraphy (BS) supports clinically relevant changes in MBC management. Therefore, we retrospectively compared management recommendations based on bone lesion assessment by 18 F-FDG PET plus contrast-enhanced CT (ceCT) or BS plus ceCT, for patients with newly diagnosed MBC. Methods: Baseline ceCT, BS, and 18 F-FDG PET for all patients included in the IMPACT-MBC study (NCT01957332) at the University Medical Center Groningen were reviewed for bone lesions. If bone lesions were found by any imaging modality, virtual MBC management recommendations were made by a multidisciplinary expert panel, based on either 18 F-FDG PET plus ceCT or BS plus ceCT. The panel had access to standard clinicopathologic information and baseline imaging findings outside the skeleton. Clinically relevant management differences between the 2 recommendations were defined either as different treatment intent (curative, noncurative, or unable to determine) or as different systemic or local treatment. If no bone lesions were found by any imaging modality, the patients were included in the analyses without expert review. Results: In total, 3,473 unequivocal bone lesions were identified in 102 evaluated patients (39% by ceCT, 26% by BS, and 87% by 18 F-FDG PET). Additional bone lesions on 18 F-FDG PET plus ceCT compared with BS plus ceCT led to change in MBC management recommendations in 16% of patients (95% CI, 10%-24%). BS also changed management compared with 18 F-FDG PET in 1 patient (1%; 95% CI, 0%-5%). In 26% (95% CI, 19%-36%) of patients, an additional 18 F-FDG PET exam was requested, because BS provided insufficient information. Conclusion: In this exploratory analysis of newly diagnosed MBC patients, 18 F-FDG PET versus BS to assess bone lesions resulted in clinically relevant management differences in 16% of patients. BS delivered insufficient information in over one fourth of patients, resulting in an additional request for 18 F-FDG PET. On the basis of these data, 18 F-FDG PET should be considered a primary imaging modality for assessment of bone lesions in newly diagnosed MBC., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) scans. Methods: Routine primary diagnostic 18 F-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of 18 F-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated. Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P < 0.001 and SUVmean 5.4 vs 3.7, P = 0.009, respectively). However, in multivariable analysis, high tumor lesion glucose uptake was only independently determined by number of tumor lesions ≥1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9). Conclusions: 18 F-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient., Competing Interests: Competing Interests: All authors have made substantial contributions to conducting the study and drafting, revising and approving the manuscript. All authors have declared that no competing interest exists that might interfere with the objective presentation of the research findings contained in the submitted study. The authors received no financial support for the research, authorship, and/or publication of this manuscript., (© The author(s).)

Objective: The aim of this study was to determine the adherence to consensus guidelines on preoperative imaging of patients with primary hyperparathyroidism (pHPT) in real local practice., Methods: This was a retrospective multicenter cohort study of 411 patients undergoing parathyroidectomy for pHPT from 2007 to 2017 in three referral centers., Results: In 286/411 patients (69%) the preoperative imaging workup adhered to guidelines (utilizing ultrasound and parathyroid scintigraphy). In patients in whom guidelines were followed 63% were discharged within one day versus 37% in whom guidelines were not followed ( P < .0005). The use of a bimodality imaging workup, starting with ultrasound and parathyroid scintigraphy followed by imaging upscaling aiming for anatomical and functional concordance, was a predictor for the performance of a minimally invasive parathyroidectomy (OR 4.098, 95% CI 2.296-7.315, P < .0005)., Conclusion: The level of compliance to preoperative imaging guidelines is suboptimal in this population. Patients in whom adherence was achieved showed a shorter length of stay. More education of physicians is required regarding the appropriate preoperative imaging workup in pHPT., Level of Evidence: 2b (individual cohort study)., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131 I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group ( p  = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) μg/L vs. 1.6 (IQR 0.6-3.1) μg/L, respectively, p  = 0.244]. The cumulative dose of 131 I was not associated with AMH levels in DTC survivors ( r s  = 0.210, p  = 0.130). Conclusions: Female survivors of DTC who received 131 I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure.

Background: PET-based tumor delineation is an error prone and labor intensive part of image analysis. Especially for patients with advanced disease showing bulky tumor FDG load, segmentations are challenging. Reducing the amount of user-interaction in the segmentation might help to facilitate segmentation tasks especially when labeling bulky and complex tumors. Therefore, this study reports on segmentation workflows/strategies that may reduce the inter-observer variability for large tumors with complex shapes with different levels of user-interaction., Methods: Twenty PET images of bulky tumors were delineated independently by six observers using four strategies: (I) manual, (II) interactive threshold-based, (III) interactive threshold-based segmentation with the additional presentation of the PET-gradient image and (IV) the selection of the most reasonable result out of four established semi-automatic segmentation algorithms (Select-the-best approach). The segmentations were compared using Jaccard coefficients (JC) and percentage volume differences. To obtain a reference standard, a majority vote (MV) segmentation was calculated including all segmentations of experienced observers. Performed and MV segmentations were compared regarding positive predictive value (PPV), sensitivity (SE), and percentage volume differences., Results: The results show that with decreasing user-interaction the inter-observer variability decreases. JC values and percentage volume differences of Select-the-best and a workflow including gradient information were significantly better than the measurements of the other segmentation strategies (p-value<0.01). Interactive threshold-based and manual segmentations also result in significant lower and more variable PPV/SE values when compared with the MV segmentation., Conclusions: FDG PET segmentations of bulky tumors using strategies with lower user-interaction showed less inter-observer variability. None of the methods led to good results in all cases, but use of either the gradient or the Select-the-best workflow did outperform the other strategies tested and may be a good candidate for fast and reliable labeling of bulky and heterogeneous tumors., Competing Interests: The authors declared that no competing interests exist.

Immune checkpoint inhibitors (ICIs) have substantially changed the field of oncology over the past few years. ICIs offer an alternative treatment strategy by exploiting the patients' immune system, resulting in a T cell mediated anti-tumor response. These therapies are effective in multiple different tumor types. Unfortunately, a substantial group of patients do not respond to ICIs. Molecular imaging, using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide non-invasive whole-body visualization of tumor and immune cell characteristics and might support patient selection or response evaluations for ICI therapies. In this review, recent studies with 18 F-fluorodeoxyglucose-PET imaging, imaging of immune checkpoints and imaging of immune cells will be discussed. These studies are until now mainly exploratory, but the first results suggest that molecular imaging biomarkers could have a role in the evaluation of ICI therapy., Competing Interests: Competing Interests: E.G.E. de Vries reports institutional financial support for her advisory role from Daiichi Sankyo, Merck, NSABP, Pfizer, Sanofi, Synthon and for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Roche, Synthon. S.F. Oosting reports institutional financial support for clinical trials or contracted research from Celldex, Pfizer, Novartis, Bristol Myers Squibb, Kura Oncology, MedImmune, Roche, Merck Sharp & Dohme. A.J. van der Wekken reports institutional financial support for his advisory role from Pfizer, Boehringer-Ingelheim, Roche (diagnostics), Astra Zeneca and institutional financial support for clinical trials from AstraZeneca. All remaining authors have declared no conflicts of interest., (© The author(s).)

Purpose: Neuroendocrine tumors (NETs) can produce neuroendocrine amines resulting in symptoms. Selecting the most active amine-producing tumor lesions for local treatment might be beneficial for patients with metastatic small intestinal NET. Tumor burden correlates with catecholamine pathway activity. We analyzed interlesional heterogeneity with F-DOPA PET scans in patients with small intestinal NET and investigated if lesions with substantially higher F-DOPA uptake could be identified., Methods: In this retrospective, observational study, the F-DOPA uptake was calculated by dividing SUVpeak of the lesion by the SUVmean of the background organ. The magnitude of heterogeneity between lesions within a patient was calculated by dividing the lesion with the highest by the one with the lowest F-DOPA uptake. Lesions with a higher F-DOPA uptake than the upper inner or outer fence (>1.5 or 3 times the interquartile range above the third quartile) were defined as lesions with mild or extreme high F-DOPA uptake, respectively, and presence of these was determined in patients with 10 lesions or more., Results: F-DOPA was detected over 680 lesions in 38 patients, of which 35 were serotonin producing. F-DOPA uptake varied with a median of 8-fold up to 44-fold between lesions within a patient. In 12 of 20 evaluable patients, lesions with mild high F-DOPA uptake were found, and in 5, lesions with extreme high F-DOPA uptake., Conclusions: F-DOPA-PET showed considerable heterogeneity in F-DOPA uptake between tumor lesions and identified lesions within patients with mild or extreme high F-DOPA uptake.

Purpose: In-vivo quantification of tumor uptake of 89-zirconium ( 89 Zr)-labelled monoclonal antibodies (mAbs) with PET provides a potential tool in strategies to optimize tumor targeting and therapeutic efficacy. A specific challenge for 89 Zr-immuno-PET is low tumor contrast. This is expected to result in interobserver variation in tumor delineation. Therefore, the aim of this study was to determine interobserver reproducibility of tumor uptake measures by tumor delineation on 89 Zr-immuno-PET scans., Methods: Data were obtained from previously published clinical studies performed with 89 Zr-rituximab, 89 Zr-cetuximab and 89 Zr-trastuzumab. Tumor lesions on 89 Zr-immuno-PET were identified as focal uptake exceeding local background by a nuclear medicine physician. Three observers independently manually delineated volumes of interest (VOI). Maximum, peak and mean standardized uptake values (SUV max , SUV peak and SUV mean ) were used to quantify tumor uptake. Interobserver variability was expressed as the coefficient of variation (CoV). The performance of semi-automatic VOI delineation using 50% of background-corrected AC peak was described., Results: In total, 103 VOI were delineated (3-6 days post injection (D3-D6)). Tumor uptake (median, interquartile range) was 9.2 (5.2-12.6), 6.9 (4.0-9.6) and 5.5 (3.3-7.8) for SUV max , SUV peak and SUV mean. Interobserver variability was 0% (0-12), 0% (0-2) and 7% (5-14), respectively (n = 103). The success rate of the semi-automatic method was 45%. Inclusion of background was the main reason for failure of semi-automatic VOI., Conclusions: This study shows that interobserver reproducibility of tumor uptake quantification on 89 Zr-immuno-PET was excellent for SUV max and SUV peak using a standardized manual procedure for tumor segmentation. Semi-automatic delineation was not robust due to limited tumor contrast.

Purpose: The main objective of this preliminary analysis of the IMaging PAtients for Cancer drug selecTion (IMPACT)-renal cell cancer (RCC) study is to evaluate the lesion detection of baseline contrast-enhanced CT, [ 89 Zr]Zr-DFO-girentuximab-PET/CT and [ 18 F]FDG-PET/CT in detecting ccRCC lesions in patients with a good or intermediate prognosis metastatic clear cell renal cell carcinoma (mccRCC) according to the International Metastatic Database Consortium (IMDC) risk model., Methods: Between February 2015 and March 2018, 42 newly diagnosed mccRCC patients with good or intermediate prognosis, eligible for watchful waiting, were included. Patients underwent CT, [ 89 Zr]Zr-DFO-girentuximab-PET/CT and [ 18 F]FDG-PET/CT at baseline. Scans were independently reviewed and lesions of ≥10 mm and lymph nodes of ≥15 mm at CT were analyzed. For lesions with [ 89 Zr]Zr-DFO-girentuximab or [ 18 F]FDG-uptake visually exceeding background uptake, maximum standardized uptake values (SUV max ) were measured., Results: A total of 449 lesions were detected by ≥1 modality (median per patient: 7; ICR 4.25-12.75) of which 42% were in lung, 22% in lymph nodes and 10% in bone. Combined [ 89 Zr]Zr-DFO-girentuximab-PET/CT and CT detected more lesions than CT alone: 91% (95%CI: 87-94) versus 56% (95%CI: 50-62, p = 0.001), respectively, and more than CT and [ 18 F]FDG-PET/CT combined (84% (95%CI:79-88, p < 0.005). Both PET/CTs detected more bone and soft tissue lesions compared to CT alone., Conclusions: The addition of [ 89 Zr]Zr-DFO-girentuximab-PET/CT and [ 18 F]FDG-PET/CT to CT increases lesion detection compared to CT alone in newly diagnosed good and intermediate prognosis mccRCC patients eligible for watchful waiting.

Purpose: To evaluate the optimal tracer uptake time, the minimal amount of radioactivity and the inter-observer agreement for 11 C-choline positron emission tomography/computed tomography (PET/CT) in patients with primary hyperparathyroidism (pHPT)., Methods: Twenty-one patients with biochemically proven pHPT were retrospectively studied after injection of 6.3 ± 1.2 MBq/kg 11 C-choline. PET data of the first nine patients, scanned for up to 60 min, were reconstructed in 10-min frames from 10- to 60-min postinjection (p.i.), mimicking varying 11 C-choline uptake times. Parathyroid adenoma to background contrast ratios were calculated and compared, using standardized uptake values (SUVs). Data was reconstructed with varying scan durations (1, 2.5, 5, and 10 min) at 20-30-min p.i. (established optimal uptake time), mimicking less administered radioactivity. To establish the minimal required radioactivity, the SUVs in the shorter scan durations (1, 2.5, and 5 min) were compared to the 10-min scan duration to determine whether increased variability and/or statistical differences were observed. Four observers analyzed the 11 C-choline PET/CT in four randomized rounds for all patients., Results: SUVpeak of the adenoma decreased from 30 to 40 p.i. onwards. All adenoma/background contrast ratios did not differ from 20- to 30-min p.i. onwards. The SUVs of adenoma in the scan duration of 1, 2.5, and 5 min all differed significantly from the same SUV in the 10-min scan duration (all p = 0.012). However, the difference in absolute SUV adenoma values was well below 10% and therefore not considered clinically significant. The inter-observer analysis showed that the Fleiss' kappa of the 1-min scan were classified as "moderate," while these values were classified as "good" in the 2.5-, 5-, and 10-min scan duration. Observers scored lower certainty scores in the 1- and 2.5-min scans compared to the 5- and 10-min scan durations., Conclusion: The optimal time to start PET/CT scanning in patients with pHPT is 20 min after mean injection of 6.3 MBq/kg 11 C-choline, with a recommended scan duration of at least 5 min. Alternatively, the radioactivity dose can be lowered by 50% while keeping a 10-min scan duration without losing the accuracy of 11 C-choline PET/CT interpretation.

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers., Materials and Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%)., Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible., Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Secondary protein-losing enteropathy (PLE) is a rare complication following pediatric liver transplantation (LT), mostly related to venous outflow obstruction of the liver. Here, we discuss a thus far unknown cause of secondary PLE following pediatric LT. A 7-month-old boy underwent LT with biliary anastomosis using a Roux-en-Y jejunal loop. Eleven months later he developed PLE. Routine diagnostic workup was negative. No hepatic outflow obstruction was detected during catheterization. Although the hepatic venous pressure gradient was slightly increased (10 mm Hg), there were no clinical signs of portal hypertension. Albumin scintigraphy with specific early recordings suggested focal albumin intestinal entry in the jejunal Roux-en-Y loop. Local bacterial overgrowth or local lymphangiectasia, possibly due to (venous) congestion, was considered. Treatment with metronidazole did not improve albumin loss. Next, surgical revision of the jejunal Roux-en-Y loop was performed. The explanted loop contained a small abnormal area with a thin hyperemic mucosa, near the former anastomosis. Histopathological analysis showed changes both in the blood vessels and the lymphatic vessels with focal deeper chronic active inflammation resulting in congestion of vessels, hampering lymphatic outflow leading to lymphangiectasia and patchy distortion of lymphatic vessels. Following surgical revision, secondary PLE disappeared, up to now, 1.5 year post revision., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose: Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in 9 patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), an approximately 55 kDa bispecific T-cell engager (BiTE®) directed against carcinoembryonic antigen (CEA) on tumor cells and cluster of differentiation 3 (CD3) on T-cells., Experimental Design: 89 Zr-labeled AMG 211 as tracer was administered alone or with cold AMG 211, for PET imaging before and/or during AMG 211 treatment., Results: Before AMG 211 treatment, the optimal imaging dose was 200-μg 89 Zr-AMG 211 + 1,800-μg cold AMG 211. At 3 hours, the highest blood pool standardized uptake value (SUV) mean was 4.0, and tracer serum half-life was 3.3 hours. CD3-mediated uptake was clearly observed in CD3-rich lymphoid tissues including spleen and bone marrow (SUV mean 3.2 and 1.8, respectively), and the SUV mean decreased more slowly than in other healthy tissues. 89 Zr-AMG 211 remained intact in plasma and was excreted predominantly via the kidneys in degraded forms. Of 43 visible tumor lesions, 37 were PET quantifiable, with a SUV max of 4.0 [interquartile range (IQR) 2.7-4.4] at 3 hours using the optimal imaging dose. The tracer uptake differed between tumor lesions 5-fold within and 9-fold between patients. During AMG 211 treatment, tracer was present in the blood pool, whereas tumor lesions were not visualized, possibly reflecting target saturation., Conclusions: This first-in-human study shows high, specific 89 Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter- and intraindividual heterogeneous tumor uptake., (©2019 American Association for Cancer Research.)

Background: Thyroglobulin (Tg) is an established tumor marker in differentiated thyroid carcinoma (DTC). However, Tg assays can be subject to interference by autoantibodies against Tg (TgAbs). No clinical consensus exists on the cutoff value of TgAb positivity and its relationship to Tg assay interference. The aims of this study were to investigate the most applicable cutoff value for TgAb positivity in clinical practice and to evaluate whether tumor characteristics differ between TgAb+ and TgAb- patients during ablation therapy using the manufacturer's cutoff (MCO) and institutional cutoff (ICO)., Methods: This single-center cohort study included 230 DTC patients diagnosed between January 2006 and December 2014. Serum Tg and TgAbs were measured with the Tg-IRMA (Thermo Fisher Scientific) and ARCHITECT Anti-Tg (Abbott Laboratories) assays. Patients were divided into TgAb- and TgAb+ based on the limit of detection (LoD; ≥0.07 IU/mL), functional sensitivity (FS; ≥0.31 IU/mL), MCO (≥4.11 IU/mL), and ICO (≥10 IU/mL)., Results: All patients were TgAb+ based on the LoD; one patient was negative on FS. Fifty-five (23.9%) and 34 (14.8%) patients had TgAbs above the MCO and ICO, respectively. Histology, presence of multifocality, tumor-node-metastasis, and American Thyroid Assocation risk stratification did not differ between TgAb- and TgAb+ patients using MCO and ICO during ablation., Conclusions: This study supports the use of a higher cutoff value than that of the FS for TgAb positivity in clinical settings. The LoD and FS are too sensitive to discriminate TgAb positivity and negativity in DTC patients during ablation therapy. The presence of TgAbs during ablation is not related to tumor characteristics and risk profile. This implies that TgAb positivity should not be considered a separate risk factor.

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit 1,2 . Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection 3-11 . Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients 12,13 . Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.