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Cystic fibrosis (CF) is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance, and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to the limited accessibility of the small airways with the current single-photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [ 68 Ga]-tagged macroaggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down a few minutes after delivery. Cystic fibrosis pigs' small airways cleared significantly less than non-CF pigs' small airways (non-CF 25.1 ± 3.1% vs. CF 14.6 ± 0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue uridine-5'-triphosphate (UTP) further impaired clearance (non-CF with UTP 20.9 ± 0.3% vs. CF with UTP 13.0 ± 1.8%). None of the cystic fibrosis pigs treated with UTP ( n = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists. NEW & NOTEWORTHY We developed a novel positron emission tomography scan assay with unprecedented temporal and spatial resolution to measure mucociliary clearance in the small airways. We proved a long-standing but unproven assertion that mucociliary clearance is inherently abnormal in the small airways of newborn cystic fibrosis piglets that are otherwise free of infection or inflammation. This technique can be easily extended to other airway diseases such as asthma, idiopathic pulmonary fibrosis, or chronic obstructive pulmonary disease.

The development of artificial intelligence (AI) within nuclear imaging involves several ethically fraught components at different stages of the machine learning pipeline, including during data collection, model training and validation, and clinical use. Drawing on the traditional principles of medical and research ethics, and highlighting the need to ensure health justice, the AI task force of the Society of Nuclear Medicine and Molecular Imaging has identified 4 major ethical risks: privacy of data subjects, data quality and model efficacy, fairness toward marginalized populations, and transparency of clinical performance. We provide preliminary recommendations to developers of AI-driven medical devices for mitigating the impact of these risks on patients and populations., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

The deployment of artificial intelligence (AI) has the potential to make nuclear medicine and medical imaging faster, cheaper, and both more effective and more accessible. This is possible, however, only if clinicians and patients feel that these AI medical devices (AIMDs) are trustworthy. Highlighting the need to ensure health justice by fairly distributing benefits and burdens while respecting individual patients' rights, the AI Task Force of the Society of Nuclear Medicine and Molecular Imaging has identified 4 major ethical risks that arise during the deployment of AIMD: autonomy of patients and clinicians, transparency of clinical performance and limitations, fairness toward marginalized populations, and accountability of physicians and developers. We provide preliminary recommendations for governing these ethical risks to realize the promise of AIMD for patients and populations., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

There has been significant recent interest in understanding both the frequency of nuclear medicine injection infiltration and the potential for negative impact, including skin injury. However, no large-scale study has yet correlated visualized injection site activity with actual activity measurement of an infiltrate. Additionally, current skin dosimetry approaches lack sufficient detail to account for critical factors that impact the dose to the radiosensitive epidermis. Methods: From 10 imaging sites, 1,000 PET/CT patient studies were retrospectively collected. At each site, consecutive patients with the injection site in the field of view were used. The radiopharmaceutical, injected activity, time of injection and imaging, injection site, and injection method were recorded. Net injection site activity was calculated from volumes of interest. Monte Carlo image-based absorbed dose calculations were performed using the actual geometry from a patient with a minor infiltration. The simulation model used an activity distribution in the skin microanatomy based on known properties of subcutaneous fat, dermis, and epidermis. Simulations using several subcutaneous fat-to-dermis concentration ratios were performed. Absorbed dose to the epidermis, dermis, and fat were calculated along with relative γ- and β-contributions, and these findings were extrapolated to a hypothetical worst-case (470 MBq) full-injection infiltration. Results: Only 6 of 1,000 patients had activity at the injection site in excess of 370 kBq (10 μCi), with no activities greater than 1.7 MBq (45 μCi). In 460 of 1,000 patients, activity at the injection site was clearly visualized. However, quantitative assessment of activities averaged only 34 kBq (0.9 μCi), representing 0.008% of the injected activity. Calculations for the extrapolated 470-MBq infiltration resulted in a hypothetical absorbed dose to the epidermis of below 1 Gy, a factor of 2 lower than what is required for deterministic skin reactions. Analysis of the dose distribution demonstrates that the dermis acts as a β-shield for the radiation-sensitive epidermis. Dermal shielding is highly effective for low-energy 18 F positrons but less so with the higher-energy positrons of 68 Ga. Conclusion: When quantitative activity measurement criteria are used rather than visual, the frequency of PET infiltration appears substantially below frequencies previously published. Shallow doses to the epidermis from infiltration events are also likely substantially lower than previously reported because of absorption of β-particles in the dermis., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Historically, patient datasets have been used to develop and validate various reconstruction algorithms for PET/MRI and PET/CT. To enable such algorithm development, without the need for acquiring hundreds of patient exams, in this article we demonstrate a deep learning technique to generate synthetic but realistic whole-body PET sinograms from abundantly available whole-body MRI. Specifically, we use a dataset of 56 18 F-FDG-PET/MRI exams to train a 3-D residual UNet to predict physiologic PET uptake from whole-body T1-weighted MRI. In training, we implemented a balanced loss function to generate realistic uptake across a large dynamic range and computed losses along tomographic lines of response to mimic the PET acquisition. The predicted PET images are forward projected to produce synthetic PET (sPET) time-of-flight (ToF) sinograms that can be used with vendor-provided PET reconstruction algorithms, including using CT-based attenuation correction (CTAC) and MR-based attenuation correction (MRAC). The resulting synthetic data recapitulates physiologic 18 F-FDG uptake, e.g., high uptake localized to the brain and bladder, as well as uptake in liver, kidneys, heart, and muscle. To simulate abnormalities with high uptake, we also insert synthetic lesions. We demonstrate that this sPET data can be used interchangeably with real PET data for the PET quantification task of comparing CTAC and MRAC methods, achieving ≤ 7.6% error in mean-SUV compared to using real data. These results together show that the proposed sPET data pipeline can be reasonably used for development, evaluation, and validation of PET/MRI reconstruction methods.

Trustworthiness is a core tenet of medicine. The patient-physician relationship is evolving from a dyad to a broader ecosystem of health care. With the emergence of artificial intelligence (AI) in medicine, the elements of trust must be revisited. We envision a road map for the establishment of trustworthy AI ecosystems in nuclear medicine. In this report, AI is contextualized in the history of technologic revolutions. Opportunities for AI applications in nuclear medicine related to diagnosis, therapy, and workflow efficiency, as well as emerging challenges and critical responsibilities, are discussed. Establishing and maintaining leadership in AI require a concerted effort to promote the rational and safe deployment of this innovative technology by engaging patients, nuclear medicine physicians, scientists, technologists, and referring providers, among other stakeholders, while protecting our patients and society. This strategic plan was prepared by the AI task force of the Society of Nuclear Medicine and Molecular Imaging., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

A standardized approach to acquiring amyloid PET images increases their value as disease and drug response biomarkers. Most 18 F PET amyloid brain scans often are assessed only visually (per regulatory labels), with a binary decision indicating the presence or absence of Alzheimer disease amyloid pathology. Minimizing technical variance allows precise, quantitative SUV ratios (SUVRs) for early detection of β-amyloid plaques and allows the effectiveness of antiamyloid treatments to be assessed with serial studies. Methods: The Quantitative Imaging Biomarkers Alliance amyloid PET biomarker committee developed and validated a profile to characterize and reduce the variability of SUVRs, increasing statistical power for these assessments. Results: On achieving conformance, sites can justify a claim that brain amyloid burden reflected by the SUVR is measurable to a within-subject coefficient of variation of no more than 1.94% when the same radiopharmaceutical, scanner, acquisition, and analysis protocols are used. Conclusion: This overview explains the claim, requirements, barriers, and potential future developments of the profile to achieve precision in clinical and research amyloid PET imaging., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

An important need exists for strategies to perform rigorous objective clinical-task-based evaluation of artificial intelligence (AI) algorithms for nuclear medicine. To address this need, we propose a 4-class framework to evaluate AI algorithms for promise, technical task-specific efficacy, clinical decision making, and postdeployment efficacy. We provide best practices to evaluate AI algorithms for each of these classes. Each class of evaluation yields a claim that provides a descriptive performance of the AI algorithm. Key best practices are tabulated as the RELAINCE (Recommendations for EvaLuation of AI for NuClear medicinE) guidelines. The report was prepared by the Society of Nuclear Medicine and Molecular Imaging AI Task Force Evaluation team, which consisted of nuclear-medicine physicians, physicists, computational imaging scientists, and representatives from industry and regulatory agencies., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Molecular tumor volume (MTV) is a parameter of interest in prostate cancer for assessing total disease burden on prostate-specific membrane antigen (PSMA) PET. Although software segmentation tools can delineate whole-body MTV, a necessary step toward meaningful monitoring of total tumor burden and treatment response through PET is establishing the repeatability of these metrics. The present study assessed the repeatability of total MTV and related metrics for 68 Ga-PSMA-HBED-CC in prostate cancer. Methods: Eighteen patients from a prior repeatability study who underwent 2 test-retest PSMA PET/CT scans within a mean interval of 5 d were reanalyzed. Within-subject coefficient of variation and repeatability coefficients (RCs) were analyzed on a per-lesion and per-patient basis. For the per-lesion analysis, individual lesions were segmented for analysis by a single reader. For the per-patient analysis, subgroups of up to 10 lesions (single reader) and the total tumor volume per patient were segmented (independently by 2 readers). Image parameters were MTV, SUV max , SUV peak , SUV mean , total lesion PSMA, and the related metric PSMA quotient (which integrates lesion volume and PSMA avidity). Results: In total, 192 segmentations were analyzed for the per-lesion analysis and 1,662 segmentations for the per-patient analysis (combining the 2 readers and 2 scans). The RC of the MTV of single lesions was 77% (95% CI, 63%-96%). The RC improved to 33% after aggregation of up to 10 manually selected lesions into subgroups assessed per patient (95% CI, 25%-46%). The RC of the semiautomatic MTV total (the sum of all voxels in the whole-body total tumor segmentation per patient) was 35% (95% CI, 25%-50%), the Bland-Altman bias was -6.70 (95% CI, -14.32-0.93). Alternating readers between scans led to a comparable RC of 37% (95% CI, 28%-49%) for MTV total , meaning that the metric is robust between scanning sessions and between readers. Conclusion: 68 Ga-PSMA-HBED-CC PET-derived semiautomatic MTV total is repeatable and reader-independent, with a change of ±35% representing a true change in tumor volume. Volumetry of single manually selected lesions has considerably lower repeatability, and volumetry based on subgroups of these lesions, although showing acceptable repeatability, is less systematic. The semiautomatic analysis of MTV total used in this study offers an efficient and robust means of assessing response to therapy., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a "harmonized" alongside a "standard" dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on the images with the highest image noise as compared to the images with the lowest image noise. Using the harmonized dataset significantly improved the feature agreement for five of the six investigated feature classes over the standard dataset. For three feature classes, high feature agreement corresponded with higher sensitivity to the different patterns, suggesting a way to select suitable features for predictive models.

The nuclear medicine field has seen a rapid expansion of academic and commercial interest in developing artificial intelligence (AI) algorithms. Users and developers can avoid some of the pitfalls of AI by recognizing and following best practices in AI algorithm development. In this article, recommendations on technical best practices for developing AI algorithms in nuclear medicine are provided, beginning with general recommendations and then continuing with descriptions of how one might practice these principles for specific topics within nuclear medicine. This report was produced by the AI Task Force of the Society of Nuclear Medicine and Molecular Imaging., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The purpose of this work was to develop and validate a deep convolutional neural network (CNN) approach for the automated pelvis segmentation in computed tomography (CT) scans to enable the quantification of active pelvic bone marrow by means of Fluorothymidine F-18 (FLT) tracer uptake measurement in positron emission tomography (PET) scans. This quantification is a critical step in calculating bone marrow dose for radiopharmaceutical therapy clinical applications as well as external beam radiation doses., Methods: An approach for the combined localization and segmentation of the pelvis in CT volumes of varying sizes, ranging from full-body to pelvis CT scans, was developed that utilizes a novel CNN architecture in combination with a random sampling strategy. The method was validated on 34 planning CT scans and 106 full-body FLT PET-CT scans using a cross-validation strategy. Specifically, two different training and CNN application options were studied, quantitatively assessed, and statistically compared., Results: The proposed method was able to successfully locate and segment the pelvis in all test cases. On all data sets, an average Dice coefficient of 0.9396 ± $\pm$ 0.0182 or better was achieved. The relative tracer uptake measurement error ranged between 0.065% and 0.204%. The proposed approach is time-efficient and shows a reduction in runtime of up to 95% compared to a standard U-Net-based approach without a localization component., Conclusions: The proposed method enables the efficient calculation of FLT uptake in the pelvis. Thus, it represents a valuable tool to facilitate bone marrow preserving adaptive radiation therapy and radiopharmaceutical dose calculation. Furthermore, the method can be adapted to process other bone structures as well as organs., (© 2022 American Association of Physicists in Medicine.)

Objective: Simultaneous PET/MRIs vary in their quantitative PET performance due to inherent differences in the physical systems and differences in the image reconstruction implementation. This variability in quantitative accuracy confounds the ability to meaningfully combine and compare data across scanners. In this work, we define image reconstruction parameters that lead to comparable contrast recovery curves across simultaneous PET/MRI systems., Method: The NEMA NU-2 image quality phantom was imaged on one GE Signa and on one Siemens mMR PET/MRI scanner. The phantom was imaged at 9.7:1 contrast with standard spheres (diameter 10, 13, 17, 22, 28, 37 mm) and with custom spheres (diameter: 8.5, 11.5, 15, 25, 32.5, 44 mm) using a standardized methodology. Analysis was performed on a 30 min listmode data acquisition and on 6 realizations of 5 min from the listmode data. Images were reconstructed with the manufacturer provided iterative image reconstruction algorithms with and without point spread function (PSF) modeling. For both scanners, a post-reconstruction Gaussian filter of 3-7 mm in steps of 1 mm was applied. Attenuation correction was provided from a scaled computed tomography (CT) image of the phantom registered to the MR-based attenuation images and verified to align on the non-attenuation corrected PET images. For each of these image reconstruction parameter sets, contrast recovery coefficients (CRCs) were determined for the SUV mean , SUV max and SUV peak for each sphere. A hybrid metric combining the root-mean-squared discrepancy (RMSD) and the absolute CRC values was used to simultaneously optimize for best match in CRC between the two scanners while simultaneously weighting toward higher resolution reconstructions. The image reconstruction parameter set was identified as the best candidate reconstruction for each vendor for harmonized PET image reconstruction., Results: The range of clinically relevant image reconstruction parameters demonstrated widely different quantitative performance across cameras. The best match of CRC curves was obtained at the lowest RMSD values with: for CRC mean , 2 iterations-7 mm filter on the GE Signa and 4 iterations-6 mm filter on the Siemens mMR, for CRC max , 4 iterations-6 mm filter on the GE Signa, 4 iterations-5 mm filter on the Siemens mMR and for CRC peak , 4 iterations-7 mm filter with PSF on the GE Signa and 4 iterations-7 mm filter on the Siemens mMR. Over all reconstructions, the RMSD between CRCs was 1.8%, 3.6% and 2.9% for CRC mean, max and peak, respectively. The solution of 2 iterations-3 mm on the GE Signa and 4 iterations-3 mm on Siemens mMR, both with PSF, led to simultaneous harmonization and with high CRC and low RMSD for CRC mean, max and peak with RMSD values of 2.8%, 5.8% and 3.2%, respectively., Conclusions: For two commercially available PET/MRI scanners, user-selectable parameters that control iterative updates, image smoothing and PSF modeling provide a range of contrast recovery curves that allow harmonization in harmonization strategies of optimal match in CRC or high CRC values. This work demonstrates that nearly identical CRC curves can be obtained on different commercially available scanners by selecting appropriate image reconstruction parameters., (© 2021. The Author(s).)

Purpose: One major challenge facing simultaneous positron emission tomography (PET)/ magnetic resonance imaging (MRI) is PET attenuation correction (AC) measurement and evaluation of its accuracy. There is a crucial need for the evaluation of current and emergent PET AC methodologies in terms of absolute quantitative accuracy in the reconstructed PET images. Approach: To address this need, we developed and evaluated a lesion insertion tool for PET/MRI that will facilitate this evaluation process. This tool was developed for the Biograph mMR and evaluated using phantom and patient data. Contrast recovery coefficients (CRC) from the NEMA IEC phantom of synthesized lesions were compared to measurements. In addition, SUV biases of lesions inserted in human brain and pelvis images were assessed from PET images reconstructed with MRI-based AC (MRAC) and CT-based AC (CTAC). Results: For cross-comparison PET/MRI scanners AC evaluation, we demonstrated that the developed lesion insertion tool can be harmonized with the GE-SIGNA lesion insertion tool. About < 3 % CRC curves difference between simulation and measurement was achieved. An average of 1.6% between harmonized simulated CRC curves obtained with mMR and SIGNA lesion insertion tools was achieved. A range of - 5 % to 12% MRAC to CTAC SUV bias was respectively achieved in the vicinity and inside bone tissues in patient images in two anatomical regions, the brain, and pelvis. Conclusions: A lesion insertion tool was developed for the Biograph mMR PET/MRI scanner and harmonized with the SIGNA PET/MRI lesion insertion tool. These tools will allow for an accurate evaluation of different PET/MRI AC approaches and permit exploration of subtle attenuation correction differences across systems., (© 2021 Society of Photo-Optical Instrumentation Engineers (SPIE).)

In recent years the use of beta-emitting radiopharmaceuticals for cancer therapy has expanded rapidly following development of therapeutics for neuroendocrine tumors, prostate cancer, and other oncologic malignancies. One emerging beta-emitting radioisotope of interest for therapy is 67 Cu (t 1/2 : 2.6 d) due to its chemical equivalency with the widely-established positron-emitting isotope 64 Cu (t 1/2 : 12.7 h). In this work we evaluate both the imaging and dosimetric characteristics of 67 Cu, as well as producing the first report of SPECT/CT imaging using 67 Cu. To this end, 67 Cu was produced by photon-induced reactions on isotopically-enriched 68 Zn at the Low-Energy Accelerator Facility (LEAF) of Argonne National Laboratory, followed by bulk separation of metallic 68 Zn by sublimation and radiochemical purification by column chromatography. Gamma spectrometry was performed by efficiency-calibrated high-purity germanium (HPGe) analysis to verify absolute activity calibration and establish radionuclidic purity. Absolute activity measurements corroborated manufacturer-recommended dose-calibrator settings and no radionuclidic impurities were observed. Using the Clinical Trials Network anthropomorphic chest phantom, SPECT/CT images were acquired. Medium energy (ME) SPECT collimation was found to provide the best image quality from the primary 185 keV gamma emission of 67 Cu. Reconstructed images of 67 Cu were similar in quality to images acquired using 177 Lu. Recovery coefficients were calculated and compared against quantitative images of 99m Tc, 177 Lu, and 64 Cu within the same anthropomorphic chest phantom. Production and clinical imaging of 67 Cu appears feasible, and future studies investigating the therapeutic efficacy of 67 Cu-based radiopharmaceuticals are warranted.

Theranostics is a new and evolving combination diagnostic and/or therapeutic approach that is demonstrating efficacy for treatment of a growing number of cancers. In this approach, a diagnostic radiopharmaceutical is used in concert with positron-emission tomography (PET) or single photon emission computed tomography (SPECT) imaging to identify whether a cancer-specific membrane protein is strongly expressed on a patient's tumors. If the molecular target is detected with sufficient specificity and uptake, a therapeutic radiopharmaceutical, nearly identical to the diagnostic radiopharmaceutical except labeled with a longer-lived alpha or beta-emitting radionuclide, is administered at a therapeutic dose level to treat the cancer. Quantitative imaging methods are being used to elucidate patient-specific pharmacokinetics to select patients for whom the therapeutic radiopharmaceutical would be most beneficial. Similarly, quantitative imaging of the therapeutic radionuclide is being used to image pharmacodynamic response to therapy (cell kill) to guide personalized, patient-specific dosages designed to both reduce radiation toxicities and optimize radiotherapeutic benefit., (Copyright © 2020. Published by Elsevier Inc.)

The PET radiotracer 68 Ga-PSMA (prostate-specific membrane antigen)-HBED-CC ( N,N '-bis [2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N,N '-diacetic acid) shows potential as an imaging biomarker for recurrent and metastatic prostate cancer. The purpose of this study was to determine the repeatability of 68 Ga-PSMA-HBED-CC in a test-retest trial in subjects with metastatic prostate adenocarcinoma. Methods: Subjects with metastatic prostate cancer underwent 2 PET/CT scans with 68 Ga-PSMA-HBED-CC within 14 d (mean, 6 ± 4 d). Lesions in bone, nodes, prostate/bed, and visceral organs, as well as representative normal tissues (salivary glands and spleen), were segmented separately by 2 readers. Absolute and percentage differences in SUV max and SUV mean were calculated for all test-retest regions. Repeatability was assessed using percentage difference, within-subject coefficient of variation (wCV), repeatability coefficient (RC), and Bland-Altman analysis. Results: Eighteen subjects were evaluated, 16 of whom demonstrated local or metastatic disease on 68 Ga-PSMA-HBED-CC PET/CT. In total, 136 lesions were segmented in bone ( n = 99), nodes ( n = 27), prostate/bed ( n = 7), and viscera ( n = 3). The wCV for SUV max was 11.7% for bone lesions and 13.7% for nodes. The RC was ±32.5% SUV max for bone lesions and ±37.9% SUV max for nodal lesions, meaning 95% of the normal variability between 2 measurements will be within these numbers, so larger differences are likely attributable to true biologic changes in tumor rather than normal physiologic or measurement variability. wCV in the salivary glands and spleen was 8.9% and 10.7% SUV mean , respectively. Conclusion: Repeatability measurements for PET/CT test-retests with 68 Ga-PSMA-HBED-CC showed a wCV of 12%-14% SUV max and an RC of ±33%-38% SUV max in bone and nodal lesions. These estimates are an important aspect of 68 Ga-PSMA-HBED-CC as a quantitative imaging biomarker. These estimates are similar to those reported for 18 F-FDG, suggesting that 68 Ga-PSMA-HBED-CC PET/CT may be useful in monitoring response to therapy., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Quantitative imaging biomarkers (QIBs) provide medical image-derived intensity, texture, shape, and size features that may help characterize cancerous tumors and predict clinical outcomes. Successful clinical translation of QIBs depends on the robustness of their measurements. Biomarkers derived from positron emission tomography images are prone to measurement errors owing to differences in image processing factors such as the tumor segmentation method used to define volumes of interest over which to calculate QIBs. We illustrate a new Bayesian statistical approach to characterize the robustness of QIBs to different processing factors. Study data consist of 22 QIBs measured on 47 head and neck tumors in 10 positron emission tomography/computed tomography scans segmented manually and with semiautomated methods used by 7 institutional members of the NCI Quantitative Imaging Network. QIB performance is estimated and compared across institutions with respect to measurement errors and power to recover statistical associations with clinical outcomes. Analysis findings summarize the performance impact of different segmentation methods used by Quantitative Imaging Network members. Robustness of some advanced biomarkers was found to be similar to conventional markers, such as maximum standardized uptake value. Such similarities support current pursuits to better characterize disease and predict outcomes by developing QIBs that use more imaging information and are robust to different processing factors. Nevertheless, to ensure reproducibility of QIB measurements and measures of association with clinical outcomes, errors owing to segmentation methods need to be reduced., Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare., (© 2020 The Authors. Published by Grapho Publications, LLC.)

Purpose: To develop bone material analogues that can be used in construction of phantoms for simultaneous PET/MRI systems., Methods: Plaster was used as the basis for the bone material analogues tested in this study. It was mixed with varying concentrations of an iodinated CT contrast, a gadolinium-based MR contrast agent, and copper sulfate to modulate the attenuation properties and MRI properties (T1 and T2*). Attenuation was measured with CT and 68 Ge transmission scans, and MRI properties were measured with quantitative ultrashort echo time pulse sequences. A proof-of-concept skull was created by plaster casting., Results: Undoped plaster has a 511 keV attenuation coefficient (~0.14 cm -1 ) similar to cortical bone (0.10-0.15 cm -1 ), but slightly longer T1 (~500 ms) and T2* (~1.2 ms) MR parameters compared to bone (T1 ~ 300 ms, T2* ~ 0.4 ms). Doping with the iodinated agent resulted in increased attenuation with minimal perturbation to the MR parameters. Doping with a gadolinium chelate greatly reduced T1 and T2*, resulting in extremely short T1 values when the target T2* values were reached, while the attenuation coefficient was unchanged. Doping with copper sulfate was more selective for T2* shortening and achieved comparable T1 and T2* values to bone (after 1 week of drying), while the attenuation coefficient was unchanged., Conclusions: Plaster doped with copper sulfate is a promising bone material analogue for a PET/MRI phantom, mimicking the MR properties (T1 and T2*) and 511 keV attenuation coefficient of human cortical bone., (© 2020 American Association of Physicists in Medicine.)

The University of Iowa recently completed a 4-y expedition into the uncharted waters of the Food and Drug Administration (FDA) new-drug application (NDA) process that ultimately resulted in approval of 68 Ga-DOTATOC in August 2019. The journey was enlightening, revealing a highly structured, arcane, but rigorous regulatory approval process. The FDA proved to be an efficient, reasonable, and communicative regulatory body that achieved balance between support of the initiative and its mission-bound, process-bound duty to ensure that the application met the expected safety and efficacy standards of the agency. With several clinically valuable PET radiopharmaceuticals without intellectual property residing in regulatory limbo, without industry champions to bring them to marketing approval, there may be justification for a more concerted effort from the molecular imaging community into generating better understanding, support, and perhaps even infrastructure for the academic NDA. As a first step, this article briefly describes the start-to-finish story for 68 Ga-DOTATOC, including a description of the clinical trials, a broad overview of the structured content of the NDA document, and the distilled experiences associated with the 68 Ga-DOTATOC NDA process. It is anticipated that with sustained free sharing of information relating to the FDA drug registration process, it will prove less daunting and more efficient in future academically sponsored NDA filings for PET imaging agents., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The purpose of this work was to assess the potential of deep convolutional neural networks in automated measurement of cerebellum tracer uptake in F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scans., Methods: Three different three-dimensional (3D) convolutional neural network architectures (U-Net, V-Net, and modified U-Net) were implemented and compared regarding their performance in 3D cerebellum segmentation in FDG PET scans. For network training and testing, 134 PET scans with corresponding manual volumetric segmentations were utilized. For segmentation performance assessment, a fivefold cross-validation was used, and the Dice coefficient as well as signed and unsigned distance errors were calculated. In addition, standardized uptake value (SUV) uptake measurement performance was assessed by means of a statistical comparison to an independent reference standard. Furthermore, a comparison to a previously reported active-shape-model-based approach was performed., Results: Out of the three convolutional neural networks investigated, the modified U-Net showed significantly better segmentation performance. It achieved a Dice coefficient of 0.911 ± 0.026, a signed distance error of 0.220 ± 0.103 mm, and an unsigned distance error of 1.048 ± 0.340 mm. When compared to the independent reference standard, SUV uptake measurements produced with the modified U-Net showed no significant error in slope and intercept. The estimated reduction in total SUV measurement error was 95.1%., Conclusions: The presented work demonstrates the potential of deep convolutional neural networks in automated SUV measurement of reference regions. While it focuses on the cerebellum, utilized methods can be generalized to other reference regions like the liver or aortic arch. Future work will focus on combining lesion and reference region analysis into one approach., (© 2019 American Association of Physicists in Medicine.)

The Quantitative Imaging Biomarkers Alliance (QIBA) Profile for fluorodeoxyglucose (FDG) PET/CT imaging was created by QIBA to both characterize and reduce the variability of standardized uptake values (SUVs). The Profile provides two complementary claims on the precision of SUV measurements. First, tumor glycolytic activity as reflected by the maximum SUV (SUV max ) is measurable from FDG PET/CT with a within-subject coefficient of variation of 10%-12%. Second, a measured increase in SUV max of 39% or more, or a decrease of 28% or more, indicates that a true change has occurred with 95% confidence. Two applicable use cases are clinical trials and following individual patients in clinical practice. Other components of the Profile address the protocols and conformance standards considered necessary to achieve the performance claim. The Profile is intended for use by a broad audience; applications can range from discovery science through clinical trials to clinical practice. The goal of this report is to provide a rationale and overview of the FDG PET/CT Profile claims as well as its context, and to outline future needs and potential developments., (© RSNA, 2020 See also the editorial by Ulaner in this issue.)

Introduction: 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is now a standard diagnostic imaging test performed in patients with head and neck cancer for staging, re-staging, radiotherapy planning, and outcome assessment. Currently, quantitative analysis of FDG PET scans is limited to simple metrics like maximum standardized uptake value, metabolic tumor volume, or total lesion glycolysis, which have limited predictive value. The goal of this work was to assess the predictive potential of new (i.e., nonstandard) quantitative imaging features on head and neck cancer outcome., Methods: This retrospective study analyzed fifty-eight pre- and post-treatment FDG PET scans of patients with head and neck squamous cell cancer to calculate five standard and seventeen new features at baseline and post-treatment. Cox survival regression was used to assess the predictive potential of each quantitative imaging feature on disease-free survival., Results: Analysis showed that the post-treatment change of the average tracer uptake in the rim background region immediately adjacent to the tumor normalized by uptake in the liver represents a novel PET feature that is associated with disease-free survival (HR 1.95; 95% CI 1.27, 2.99) and has good discriminative performance (c index 0.791)., Conclusion: The reported findings define a promising new direction for quantitative imaging biomarker research in head and neck squamous cell cancer and highlight the potential role of new radiomics features in oncology decision making as part of precision medicine., Competing Interests: The authors have declared that no competing interests exist.

Radiomics is an image analysis approach for extracting large amounts of quantitative information from medical images using a variety of computational methods. Our goal was to evaluate the utility of radiomic feature analysis from 18 F-fluorothymidine positron emission tomography (FLT PET) obtained at baseline in prediction of treatment response in patients with head and neck cancer. Thirty patients with advanced-stage oropharyngeal or laryngeal cancer, treated with definitive chemoradiation therapy, underwent FLT PET imaging before treatment. In total, 377 radiomic features of FLT uptake and feature variants were extracted from volumes of interest; these features variants were defined by either the primary tumor or the total lesion burden, which consisted of the primary tumor and all FLT-avid nodes. Feature variants included normalized measurements of uptake, which were calculated by dividing lesion uptake values by the mean uptake value in the bone marrow. Feature reduction was performed using clustering to remove redundancy, leaving 172 representative features. Effects of these features on progression-free survival were modeled with Cox regression and P -values corrected for multiple comparisons. In total, 9 features were considered significant. Our results suggest that smaller, more homogenous lesions at baseline were associated with better prognosis. In addition, features extracted from total lesion burden had a higher concordance index than primary tumor features for 8 of the 9 significant features. Furthermore, total lesion burden features showed lower interobserver variability.

The use of computed tomography (CT) images to correct for photon attenuation in positron emission tomography (PET) produces unbiased patient images, but it is not optimal for synthetic materials. For test objects made from epoxy, image bias and artifacts have been observed in well-calibrated PET/CT scanners. An epoxy used in commercially available sources was infused with long-lived 68 Ge/ 68 Ga nuclide and measured on several PET/CT scanners as well as on older PET scanners that measured attenuation with 511-keV photons. Bias in attenuation maps and PET images of phantoms was measured as imaging parameters and methods varied. Changes were made to the PET reconstruction to show the influence of CT-based attenuation correction. Additional attenuation measurements were made with a new epoxy intended for use in radiology and radiation treatment whose photonic properties mimic water. PET images of solid phantoms were biased by between 3% and 24% across variations in CT X-ray energy and scanner manufacturer. Modification of the reconstruction software reduced bias, but object-dependent changes were required to generate accurate attenuation maps. The water-mimicking epoxy formulation showed behavior similar to water in limited testing. For some solid phantoms, transformation of CT data to attenuation maps is a major source of PET image bias. The transformation can be modified to accommodate synthetic materials, but our data suggest that the problem may also be addressed by using epoxy formulations that are more compatible with PET/CT imaging.

A cylinder phantom positioned at a slightly oblique angle with respect to the z -axis of a PET scanner allows for fine sampling of the edge-spread function. We show how this technique can be used to measure the spatial resolution that can be expected with clinical PET protocols, potentially providing more relevant estimates than are typically obtained with established experimental procedures. Methods: A 20-cm-diameter water-filled cylinder phantom containing a uniform 18 F solution was centrally positioned at a small angle with respect to the z -axis of a clinical PET/CT system. The oblique angle ensures that the phantom edge intersects the image matrix differently in different slices. Combining line profiles from multiple slices results in a composite profile with fine sampling. Spatial resolution was measured as the full width at half maximum (FWHM) by fitting a model to the finely sampled edge-spread functions in both radial and axial directions. The technique was validated by controlled modulation of image reconstruction parameters and by comparison with extended phantoms with fillable inserts. Separate experiments with uniform cylinders containing 18 F, 11 C, 13 N, 68 Ga, and 124 I were used to further assess the proposed method. Results: Controlled adjustment of a gaussian postreconstruction filter was accurately reflected in the measured FWHM values. Recovery coefficients derived using the cylinder FWHM values agreed closely with recovery coefficients derived from physical phantoms over a range of insert-to-background ratios, phantom geometries, and reconstruction protocols. The effect of increasing positron energy was clearly reflected in the FWHM values measured with different isotopes. Conclusion: A method has been developed for measuring the spatial resolution that is achieved with clinical PET protocols, providing more relevant estimates than are typically obtained with established procedures. The proposed method requires no special equipment and is versatile, being capable of measuring resolution for different isotopes as well as for different reconstruction protocols. The new technique promises to aid standardization of PET data acquisition by allowing a more informed selection of reconstruction parameters., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Pretherapy PET with 86 Y-DOTATOC is considered the ideal dosimetry protocol for 90 Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90 Y-DOTATOC using 90 Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90 Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90 Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m 2 ; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90 Y-DOTATOC PET/CT at 5 h after therapy and 90 Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90 Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90 Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90 Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90 Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90 Y-DOTATOC is feasible using 90 Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Quality control plays an increasingly important role in quantitative PET imaging and is typically performed using phantoms. The purpose of this work was to develop and validate a fully automated analysis method for two common PET/CT quality assurance phantoms: the NEMA NU-2 IQ and SNMMI/CTN oncology phantom. The algorithm was designed to only utilize the PET scan to enable the analysis of phantoms with thin-walled inserts., Methods: We introduce a model-based method for automated analysis of phantoms with spherical inserts. Models are first constructed for each type of phantom to be analyzed. A robust insert detection algorithm uses the model to locate all inserts inside the phantom. First, candidates for inserts are detected using a scale-space detection approach. Second, candidates are given an initial label using a score-based optimization algorithm. Third, a robust model fitting step aligns the phantom model to the initial labeling and fixes incorrect labels. Finally, the detected insert locations are refined and measurements are taken for each insert and several background regions. In addition, an approach for automated selection of NEMA and CTN phantom models is presented. The method was evaluated on a diverse set of 15 NEMA and 20 CTN phantom PET/CT scans. NEMA phantoms were filled with radioactive tracer solution at 9.7:1 activity ratio over background, and CTN phantoms were filled with 4:1 and 2:1 activity ratio over background. For quantitative evaluation, an independent reference standard was generated by two experts using PET/CT scans of the phantoms. In addition, the automated approach was compared against manual analysis, which represents the current clinical standard approach, of the PET phantom scans by four experts., Results: The automated analysis method successfully detected and measured all inserts in all test phantom scans. It is a deterministic algorithm (zero variability), and the insert detection RMS error (i.e., bias) was 0.97, 1.12, and 1.48 mm for phantom activity ratios 9.7:1, 4:1, and 2:1, respectively. For all phantoms and at all contrast ratios, the average RMS error was found to be significantly lower for the proposed automated method compared to the manual analysis of the phantom scans. The uptake measurements produced by the automated method showed high correlation with the independent reference standard (R 2 ≥ 0.9987). In addition, the average computing time for the automated method was 30.6 s and was found to be significantly lower (P ≪ 0.001) compared to manual analysis (mean: 247.8 s)., Conclusions: The proposed automated approach was found to have less error when measured against the independent reference than the manual approach. It can be easily adapted to other phantoms with spherical inserts. In addition, it eliminates inter- and intraoperator variability in PET phantom analysis and is significantly more time efficient, and therefore, represents a promising approach to facilitate and simplify PET standardization and harmonization efforts., (© 2017 American Association of Physicists in Medicine.)

68 Ga-DOTATOC, a somatostatin receptor-targeted ligand, has been used clinically in Europe over the past decade for imaging neuroendocrine tumors (NETs). It appears to be quite sensitive and effective for clinical management decision making. This metaanalysis summarizes the efficacy of 68 Ga-DOTATOC for several distinct indications and is intended to support approval of this agent by the U.S. Food and Drug Administration. Methods: The major electronic medical databases were searched for relevant papers over the period from January 2001 to November 2015. Papers were selected for review in 3 categories: clinical trials that reported sensitivity and specificity, comparison studies with 111 In-octreotide, and change of management studies. All the eligible papers underwent Quality Assessment of Diagnostic Accuracy Studies (QUADAS) assessment, which was useful in the final selection of papers for review. Results: The initial search yielded 468 papers. After detailed evaluation, 17 papers were finally selected. Five types of studies emerged: workup of patients with symptoms and biomarker findings suggestive of NET, but with negative conventional imaging (3 papers, yield was only 13%); sensitivity (12 papers; sensitivity, 92%) and specificity (7 papers; specificity, 82%); identification of site of unknown primary in patients with metastatic NET (4 papers, yield was 44%); impact on subsequent NET patient management (4 papers, change in management in 51%); and comparison with 111 In-octreotide (2 papers, sensitivity of DOTATOC on a per-lesion basis was 100%, for 111 In-octreotide it was 78.2%; specificity was not available). Safety was not explicitly addressed in any study, but there were no reports of adverse events. Conclusion: 68 Ga-DOTATOC is useful for evaluating the presence and extent in disease for staging and restaging and for assisting in treatment decision making for patients with NET. It is also effective in locating the site of an unknown primary in NET patients who present with metastatic NET, but no known primary tumor. It also appears to be more accurate than 111 In-octreotide. Although 68 Ga-DOTATOC would seem to be useful in evaluating patients with suggestive symptoms and biomarker findings, it does not perform well in this setting and has low yield. Overall, it appears to be an excellent imaging agent to assess patients with known NET and frequently leads to a change in management., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68 Ga-DOTATOC PET/CT in a single-site prospective study. The 68 Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68 Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68 Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion: 68 Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Radiomics utilizes a large number of image-derived features for quantifying tumor characteristics that can in turn be correlated with response and prognosis. Unfortunately, extraction and analysis of such image-based features is subject to measurement variability and bias. The challenge for radiomics is particularly acute in Positron Emission Tomography (PET) where limited resolution, a high noise component related to the limited stochastic nature of the raw data, and the wide variety of reconstruction options confound quantitative feature metrics. Extracted feature quality is also affected by tumor segmentation methods used to define regions over which to calculate features, making it challenging to produce consistent radiomics analysis results across multiple institutions that use different segmentation algorithms in their PET image analysis. Understanding each element contributing to these inconsistencies in quantitative image feature and metric generation is paramount for ultimate utilization of these methods in multi-institutional trials and clinical oncology decision making., Methods: To assess segmentation quality and consistency at the multi-institutional level, we conducted a study of seven institutional members of the National Cancer Institute Quantitative Imaging Network. For the study, members were asked to segment a common set of phantom PET scans acquired over a range of imaging conditions as well as a second set of head and neck cancer (HNC) PET scans. Segmentations were generated at each institution using their preferred approach. In addition, participants were asked to repeat segmentations with a time interval between initial and repeat segmentation. This procedure resulted in overall 806 phantom insert and 641 lesion segmentations. Subsequently, the volume was computed from the segmentations and compared to the corresponding reference volume by means of statistical analysis., Results: On the two test sets (phantom and HNC PET scans), the performance of the seven segmentation approaches was as follows. On the phantom test set, the mean relative volume errors ranged from 29.9 to 87.8% of the ground truth reference volumes, and the repeat difference for each institution ranged between -36.4 to 39.9%. On the HNC test set, the mean relative volume error ranged between -50.5 to 701.5%, and the repeat difference for each institution ranged between -37.7 to 31.5%. In addition, performance measures per phantom insert/lesion size categories are given in the paper. On phantom data, regression analysis resulted in coefficient of variation (CV) components of 42.5% for scanners, 26.8% for institutional approaches, 21.1% for repeated segmentations, 14.3% for relative contrasts, 5.3% for count statistics (acquisition times), and 0.0% for repeated scans. Analysis showed that the CV components for approaches and repeated segmentations were significantly larger on the HNC test set with increases by 112.7% and 102.4%, respectively., Conclusion: Analysis results underline the importance of PET scanner reconstruction harmonization and imaging protocol standardization for quantification of lesion volumes. In addition, to enable a distributed multi-site analysis of FDG PET images, harmonization of analysis approaches and operator training in combination with highly automated segmentation methods seems to be advisable. Future work will focus on quantifying the impact of segmentation variation on radiomics system performance., (© 2016 American Association of Physicists in Medicine.)

The Quantitative Imaging Network (QIN) of the National Cancer Institute (NCI) conducts research in development and validation of imaging tools and methods for predicting and evaluating clinical response to cancer therapy. Members of the network are involved in examining various imaging and image assessment parameters through network-wide cooperative projects. To more effectively use the cooperative power of the network in conducting computational challenges in benchmarking of tools and methods and collaborative projects in analytical assessment of imaging technologies, the QIN Challenge Task Force has developed policies and procedures to enhance the value of these activities by developing guidelines and leveraging NCI resources to help their administration and manage dissemination of results. Challenges and Collaborative Projects (CCPs) are further divided into technical and clinical CCPs. As the first NCI network to engage in CCPs, we anticipate a variety of CCPs to be conducted by QIN teams in the coming years. These will be aimed to benchmark advanced software tools for clinical decision support, explore new imaging biomarkers for therapeutic assessment, and establish consensus on a range of methods and protocols in support of the use of quantitative imaging to predict and assess response to cancer therapy., Competing Interests: Conflict of Interest: None reported.

Purpose: The purpose of the present prospective clinical trial was to determine the efficacy of [(18)F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity., Methods and Materials: Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose response of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity., Results: IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test)., Conclusions: IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG-PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked., (Published by Elsevier Inc.)

Purpose: The purpose of this work was to develop, validate, and compare a highly computer-aided method for the segmentation of hot lesions in head and neck 18F-FDG PET scans., Methods: A semiautomated segmentation method was developed, which transforms the segmentation problem into a graph-based optimization problem. For this purpose, a graph structure around a user-provided approximate lesion centerpoint is constructed and a suitable cost function is derived based on local image statistics. To handle frequently occurring situations that are ambiguous (e.g., lesions adjacent to each other versus lesion with inhomogeneous uptake), several segmentation modes are introduced that adapt the behavior of the base algorithm accordingly. In addition, the authors present approaches for the efficient interactive local and global refinement of initial segmentations that are based on the "just-enough-interaction" principle. For method validation, 60 PET/CT scans from 59 different subjects with 230 head and neck lesions were utilized. All patients had squamous cell carcinoma of the head and neck. A detailed comparison with the current clinically relevant standard manual segmentation approach was performed based on 2760 segmentations produced by three experts., Results: Segmentation accuracy measured by the Dice coefficient of the proposed semiautomated and standard manual segmentation approach was 0.766 and 0.764, respectively. This difference was not statistically significant (p = 0.2145). However, the intra- and interoperator standard deviations were significantly lower for the semiautomated method. In addition, the proposed method was found to be significantly faster and resulted in significantly higher intra- and interoperator segmentation agreement when compared to the manual segmentation approach., Conclusions: Lack of consistency in tumor definition is a critical barrier for radiation treatment targeting as well as for response assessment in clinical trials and in clinical oncology decision-making. The properties of the authors approach make it well suited for applications in image-guided radiation oncology, response assessment, or treatment outcome prediction.

This study aimed to examine global and regional cerebral blood flow and amyloid burden in combat veterans with and without traumatic brain injury (TBI). Cerebral blood flow (in milliliters per minute per 100 mL) was measured by quantitative [(15)O]water, and amyloid burden was measured by [(11)C]PIB imaging. Mean global cerebral blood flow was significantly lower in veterans with TBI compared with non-TBI veterans. There were essentially no differences between groups for globally normalized regional cerebral blood flow. Amyloid burden did not differ between TBI and non-TBI veterans. Veterans who have suffered a TBI have significantly lower cerebral blood flow than non-TBI controls but did not manifest increased levels of amyloid, globally or regionally.

Drawing regions of interest (ROIs) in positron emission tomography/computed tomography (PET/CT) scans of the National Electrical Manufacturers Association (NEMA) NU-2 Image Quality (IQ) phantom is a time-consuming process that allows for interuser variability in the measurements. In order to reduce operator effort and allow batch processing of IQ phantom images, we propose a fast, robust, automated algorithm for performing IQ phantom sphere localization and analysis. The algorithm is easily altered to accommodate different configurations of the IQ phantom. The proposed algorithm uses information from both the PET and CT image volumes in order to overcome the challenges of detecting the smallest spheres in the PET volume. This algorithm has been released as an open-source plug-in to the Osirix medical image viewing software package. We test the algorithm under various noise conditions, positions within the scanner, air bubbles in the phantom spheres, and scanner misalignment conditions. The proposed algorithm shows run-times between 3 and 4 min and has proven to be robust under all tested conditions, with expected sphere localization deviations of less than 0.2 mm and variations of PET ROI mean and maximum values on the order of 0.5% and 2%, respectively, over multiple PET acquisitions. We conclude that the proposed algorithm is stable when challenged with a variety of physical and imaging anomalies, and that the algorithm can be a valuable tool for those who use the NEMA NU-2 IQ phantom for PET/CT scanner acceptance testing and QA/QC.

Pharmacological ascorbate (AscH(-)) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells compared with normal cells. Positron emission tomography (PET) with the thymidine analog 3'-deoxy-3'-((18)F) fluorothymidine (FLT) enables noninvasive imaging and quantification of the proliferation fraction of tumors. We hypothesized that the rate of tumor proliferation determined by FLT-PET imaging, would be inversely proportional to tumor susceptibility to pharmacological AscH(-)-based treatments. Indeed, there was decreased FLT uptake in human pancreatic cancer cells treated with AscH(-) in vitro, and this effect was abrogated by co-treatment with catalase. In separate experiments, cells were treated with AscH(-), ionizing radiation or a combination of both. These studies demonstrated that combined AscH(-) and radiation treatment resulted in a significant decrease in FLT uptake that directly correlated with decreased clonogenic survival. MicroPET (18)F-FLT scans of mice with pre-established tumors demonstrated that AscH(-) treatment induced radiosensitization compared to radiation treatment alone. These data support testing of pharmacological ascorbate as a radiosensitizer in pancreatic cancer as well as the use of FLT-PET to monitor response to therapy.

The Uniform Protocols for Imaging in Clinical Trials (UPICT) (18)F-FDG PET/CT protocol is intended to guide the performance of whole-body FDG PET/CT studies within the context of single- and multiple-center clinical trials of oncologic therapies by providing acceptable (minimum), target, and ideal standards for all phases of imaging. The aim is to minimize variability in intra- and intersubject, intra- and interplatform, interexamination, and interinstitutional primary or derived data. The goal of this condensed version of the much larger document is to make readers aware of the general content and subject area. The document has several main subjects: context of the imaging protocol within the clinical trial; site selection, qualification, and training; subject scheduling; subject preparation; imaging-related substance preparation and administration; imaging procedure; image postprocessing; image analysis; image interpretation; archiving and distribution of data; quality control; and imaging-associated risks and risk management., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objectives: Recent technological improvements to PET imaging equipment combined with the availability of software optimized to calculate regional myocardial blood flow (MBF) and myocardial flow reserve (MFR) create a paradigm shifting opportunity to provide new clinically relevant quantitative information to cardiologists. However, clinical interpretation of the MBF and MFR is entirely dependent upon knowledge of MBF and MFR values in normal populations and subpopulations. This work reports Rb-82-based MBF and MFR measurements for a series of 49 verified cardiovascularly normal subjects as a preliminary baseline for future clinical studies., Methods: Forty-nine subjects (24F/25M, ages 41-69) with low probability for coronary artery disease and with normal exercise stress test were included. These subjects underwent rest/dipyridamole stress Rb-82 myocardial perfusion imaging using standard clinical techniques (40 mCi injection, 6-minute acquisition) using a Siemens Biograph 40 PET/CT scanner with high count rate detector option. List mode data was rehistogrammed into 26 dynamic frames (12 × 5 seconds, 6 × 10 seconds, 4 × 20 seconds, 4 × 40 seconds). Cardiac images were processed, and MBF and MFR calculated using Siemens syngo MBF, PMOD, and FlowQuant software using a single compartment Rb-82 model., Results: Global myocardial blood flow under pharmacological stress for the 24 females as measured by PMOD, syngo MBF, and FlowQuant were 3.10 ± 0.72, 2.80 ± 0.66, and 2.60 ± 0.63 mL·minute(-1)·g(-1), and for the 25 males was 2.60 ± 0.84, 2.33 ± 0.75, 2.15 ± 0.62 mL·minute(-1)·g(-1), respectively. Rest flows for PMOD, syngo MBF, and FlowQuant averaged 1.32 ± 0.42, 1.20 ± 0.33, and 1.06 ± 0.38 mL·minute(-1)·g(-1) for the female subjects, and 1.12 ± 0.29, 0.90 ± 0.26, and 0.85 ± 0.24 mL·minute(-1)·g(-1) for the males. Myocardial flow reserves for PMOD, syngo MBF, and FlowQuant for the female normals were calculated to be 2.50 ± 0.80, 2.53 ± 0.67, 2.71 ± 0.90, and 2.50 ± 1.19, 2.85 ± 1.19, 2.94 ± 1.31 mL·minute(-1)·g(-1) for males., Conclusion: Quantitative normal MBF and MFR values averaged for age and sex have been compiled for three commercial pharmacokinetic software packages. The current collection of data consisting of 49 subjects resulted in several statistically significant conclusions that support the need for a software specific, age, and sex-matched database to aid in interpretation of quantitative clinical myocardial perfusion studies.

Introduction: The goal of this study was to define the kinetics of glucose transport from maternal blood to placenta to fetus using real time imaging., Methods: Positron emission tomography (PET) imaging of the glucose-tracer [(18)F]fluorodeoxyglucose (FDG) was used to temporally and spatially define, in vivo, the kinetics of glucose transport from maternal blood into placentae and fetuses, in the late gestational gravid rat. Computed tomography (CT), with intravenous contrast, co-registered to the PET images allowed anatomic differentiation of placentae from fetal and maternal tissues., Results: FDG was rapidly taken up by placentae and subsequently appeared in fetuses with minimal temporal lag. FDG standardized uptake values in placentae and fetuses approached that of maternal brain. In both anesthetized and awake dams, one quarter of the administered FDG ultimately was accrued in the collective fetuses and placentae. Accordingly, kinetic modeling demonstrated that the placentae had very high avidity for FDG, 2-fold greater than that of the fetus and maternal brain, when accounting for the fact that fetal FDG necessarily must first be taken up by placentae. Consistent with this, placental expression of glucose transporter 1 exceeded that of all other tissues., Discussion: Fetal and placental tissues place a substantial glucose metabolic burden on the mother, owing to very high avidity of placentae for glucose coupled with the large relative mass of fetal and placental tissues., Conclusions: The placenta has a tremendous capacity to uptake and transport glucose. PET/CT imaging is an ideal means to study metabolite transport kinetics in the fetoplacental unit., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: The Clinical Trials Network (CTN) of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) operates a PET/CT phantom imaging program using the CTN's oncology clinical simulator phantom, designed to validate scanners at sites that wish to participate in oncology clinical trials. Since its inception in 2008, the CTN has collected 406 well-characterized phantom datasets from 237 scanners at 170 imaging sites covering the spectrum of commercially available PET/CT systems. The combined and collated phantom data describe a global profile of quantitative performance and variability of PET/CT data used in both clinical practice and clinical trials., Methods: Individual sites filled and imaged the CTN oncology PET phantom according to detailed instructions. Standard clinical reconstructions were requested and submitted. The phantom itself contains uniform regions suitable for scanner calibration assessment, lung fields, and 6 hot spheric lesions with diameters ranging from 7 to 20 mm at a 4:1 contrast ratio with primary background. The CTN Phantom Imaging Core evaluated the quality of the phantom fill and imaging and measured background standardized uptake values to assess scanner calibration and maximum standardized uptake values of all 6 lesions to review quantitative performance. Scanner make-and-model-specific measurements were pooled and then subdivided by reconstruction to create scanner-specific quantitative profiles., Results: Different makes and models of scanners predictably demonstrated different quantitative performance profiles including, in some cases, small calibration bias. Differences in site-specific reconstruction parameters increased the quantitative variability among similar scanners, with postreconstruction smoothing filters being the most influential parameter. Quantitative assessment of this intrascanner variability over this large collection of phantom data gives, for the first time, estimates of reconstruction variance introduced into trials from allowing trial sites to use their preferred reconstruction methodologies. Predictably, time-of-flight-enabled scanners exhibited less size-based partial-volume bias than non-time-of-flight scanners., Conclusion: The CTN scanner validation experience over the past 5 y has generated a rich, well-curated phantom dataset from which PET/CT make-and-model and reconstruction-dependent quantitative behaviors were characterized for the purposes of understanding and estimating scanner-based variances in clinical trials. These results should make it possible to identify and recommend make-and-model-specific reconstruction strategies to minimize measurement variability in cancer clinical trials., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle., Methods and Materials: Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111., Results: RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively)., Conclusions: RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the kidneys. Preliminary data of RT-GEL as a delivery modality of a radiation source to a local tumor are promising., (Published by Elsevier Inc.)

(18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the widely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.

Purpose: The authors introduce a novel method for defining standardized uptake values (SUVs) in PET∕CT based on routinely collected CT data. The goal of the study is to reduce, if possible, the variability of SUV in a heterogeneous population. Two well established methods for defining SUV are based on body weight (BW) and lean body mass, calculated as a function of height, weight, and sex with an empirical formula (LBM). The authors investigate two novel models, CT1 and CT2, that estimate the lean mass from CT Hounsfield Unit values. The authors compare the four methods, assessing the variability of hepatic SUV in (18)F-FDG studies., Methods: CT images from 252 cancer patients were segmented into regions representing lean tissues, fat, and bone. The fraction of lean tissue in the scanned region was extrapolated to the entire body with a naive method (CT1) and a method that modeled typical FDG uptake patterns (CT2). For each method, SUV-based measurements of the liver were calculated for all patients and dependence on body weight was assessed. Coefficients of variation (CVs) were evaluated. Several sub-cohorts were analyzed, including those with low and high body mass index (BMI). The extrapolation technique was tested in 19 melanoma patients who received head to toe PET∕CT scans. CT-based weight predictions were compared with actual patient weight in melanoma studies and in PET∕CT scans of pigs., Results: Only the SUV based on BW method depended significantly on body weight. CVs for the BW, LBM, CT1, and CT2 methods were, respectively, 18.0%, 15.5%, 15.9%, and 14.9%. In the high-BMI cohort, CVs were 18.2%, 16.2%, 16.2%, and 15.1%. Mean SUV of the 14 most obese patients agreed most closely with mean SUV of 120 lean patients when the CT2 method was used. SUV based on truncated CT agreed with head to toe predictions within 5% for the CT1 method and 1% for the CT2 method. CT-based weight estimate recovered 97.4% of the weight in head to toe studies of humans and 99.7% in pig studies., Conclusions: The novel CT1 and CT2 methods were less variable than the BW method and were comparable to the LBM method. SUV were little affected by missing CT data.