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We highlight emerging uses of artificial intelligence (AI) in the field of theranostics, focusing on its significant potential to enable routine and reliable personalization of radiopharmaceutical therapies (RPTs). Personalized RPTs require patient-specific dosimetry calculations accompanying therapy. Additionally we discuss the potential to exploit biological information from diagnostic and therapeutic molecular images to derive biomarkers for absorbed dose and outcome prediction; toward personalization of therapies. We try to motivate the nuclear medicine community to expand and align efforts into making routine and reliable personalization of RPTs a reality., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A new era of precision diagnostics and therapy for patients with neuroendocrine neoplasms began with the approval of somatostatin receptor (SSTR) radiopharmaceuticals for PET imaging followed by peptide receptor radionuclide therapy (PRRT). With the transition from SSTR-based γ-scintigraphy to PET, the higher sensitivity of the latter raised questions regarding the direct application of the planar scintigraphy-based Krenning score for PRRT eligibility. Also, to date, the role of SSTR PET in response assessment and predicting outcome remains under evaluation. In this comprehensive review article, we discuss the current role of SSTR PET in all aspects of neuroendocrine neoplasms, including its relation to conventional imaging, selection of patients for PRRT, and the current understanding of SSTR PET-based response assessment. We also provide a standardized reporting template for SSTR PET with a brief discussion., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The recent advances and availability of computer hardware, software tools, and massive digital data archives have enabled the rapid development of artificial intelligence (AI) applications. Concerns over whether AI tools can "communicate" decisions to radiologists and primary care physicians is of particular importance because automated clinical decisions can substantially impact patient outcome. A challenge facing the clinical implementation of AI stems from the potential lack of trust clinicians have in these predictive models. This review will expand on the existing literature on interpretability methods for deep learning and review the state-of-the-art methods for predictive uncertainty estimation for computer-assisted segmentation tasks. Last, we discuss how uncertainty can improve predictive performance and model interpretability and can act as a tool to help foster trust. Keywords: Segmentation, Quantification, Ethics, Bayesian Network (BN) © RSNA, 2021., Competing Interests: Disclosures of Conflicts of Interest: B.M. Institution received grant from Defence Research and Development Canada (grant number CFPMN2-017-McMaster) for the Innovation for Defence Excellence and Security program presented by the DRDC. K.Z. Consultant for the Centre for Probe Development and Commercialization. T.E.D. No relevant relationships. M.D.N. Data analytics consultant for MCI OneHealth; CEO and cofounder of TBI Finder., (2021 by the Radiological Society of North America, Inc.)

Purpose: 99m Tc-MDP single-photon emission computed tomography (SPECT) is an established tool for diagnosing lumbar stress, a common cause of low back pain (LBP) in pediatric patients. However, detection of small stress lesions is complicated by the low quality of SPECT, leading to significant interreader variability. The study objectives were to develop an approach based on a deep convolutional neural network (CNN) for detecting lumbar lesions in 99m Tc-MDP scans and to compare its performance to that of physicians in a localization receiver operating characteristic (LROC) study., Methods: Sixty-five lesion-absent (LA) 99m Tc-MDP studies performed in pediatric patients for evaluating LBP were retrospectively identified. Projections for an artificial focal lesion were acquired separately by imaging a 99m Tc capillary tube at multiple distances from the collimator. An approach was developed to automatically insert lesions into LA scans to obtain realistic lesion-present (LP) 99m Tc-MDP images while ensuring knowledge of the ground truth. A deep CNN was trained using 2.5D views extracted in LP and LA 99m Tc-MDP image sets. During testing, the CNN was applied in a sliding-window fashion to compute a 3D "heatmap" reporting the probability of a lesion being present at each lumbar location. The algorithm was evaluated using cross-validation on a 99m Tc-MDP test dataset which was also studied by five physicians in a LROC study. LP images in the test set were obtained by incorporating lesions at sites selected by a physician based on clinical likelihood of injury in this population., Results: The deep learning (DL) system slightly outperformed human observers, achieving an area under the LROC curve (AUC LROC ) of 0.830 (95% confidence interval [CI]: [0.758, 0.924]) compared with 0.785 (95% CI: [0.738, 0.830]) for physicians. The AUC LROC for the DL system was higher than that of two readers (difference in AUC LROC [ΔAUC LROC ] = 0.049 and 0.053) who participated to the study and slightly lower than that of two other readers (ΔAUC LROC  = -0.006 and -0.012). Another reader outperformed DL by a more substantial margin (ΔAUC LROC  = -0.053)., Conclusion: The DL system provides comparable or superior performance than physicians in localizing small 99m Tc-MDP positive lumbar lesions., (© 2021 American Association of Physicists in Medicine.)

Rationale: We evaluated K-means clustering to classify amyloid brain PETs as positive or negative., Patients and Methods: Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data., Results: Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%., Conclusions: K-means clustering may be a powerful algorithm for classifying amyloid brain PET., Competing Interests: Conflicts of interest and sources of funding: This is a multisite project of the Toronto Dementia Research Alliance partly funded by Brain Canada, The Edward Foundation, the Canadian Institutes of Health Research, the LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, and the Dr Sandra Black Centre for Brain Resilience and Recovery. Phillip H. Kuo is a consultant for Novartis, Konica Minolta, and Bayer; is a consultant and speaker for Esai and General Electric Healthcare; and received a grant from Blue Earth Diagnostics. The other authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In 2018, the National Cancer Institute and NRG Oncology partnered for the first time to host a joint workshop on systemic radiopharmaceutical therapy (RPT) to specifically address dosimetry issues and strategies for future clinical trials. The workshop focused on current dosimetric approaches for clinical trials, strategies under development that would optimize dose reporting, and future desired or optimized approaches for novel emerging radionuclides and carriers in development. In this article, we review the main approaches that are applied clinically to calculate the absorbed dose. These include absorbed doses calculated over a variety of spatial scales, including whole body, organ, suborgan, and voxel, the last 3 of which are achievable within the MIRD schema (S value) and can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This article will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biologic effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: PSMA-targeted PET/CT is a 'Next Generation Imaging' technique with superior sensitivity and specificity for detecting recurrent prostate cancer compared with conventional imaging, allowing more accurate staging and re-staging., Areas Covered: This article reviews the role of PSMA-targeted PET/CT in clinical management of men with recurrent prostate cancer., Expert Opinion: Through enhanced spatial characterization of recurrent prostate cancer, PSMA-targeted PET/CT has shown significant impact on management decisions. In particular, by identifying men with recurrence confined to the prostate or pelvic nodes, PSMA-targeted PET/CT enables selective deployment of localized salvage therapies for management of biochemical failure after primary treatment with prostatectomy or radiotherapy. In oligometastatic disease, PSMA-targeted PET/CT may improve patient selection and treatment accuracy for metastasis-directed therapy and early phase II studies show encouraging results in delaying the need for systemic therapy. Further, quantitative PSMA-targeted PET/CT for monitoring response and therapeutic PSMA-targeted radiopharmaceuticals are emerging as encouraging treatment options in the setting of castrate-resistant disease.

Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) is increasingly being used worldwide as part of the clinical workup for men with prostate cancer. With high overall accuracy for the detection of prostate cancer, PSMA-targeted PET has an increasingly established role in the setting of biochemical failure after primary therapy and an evolving role in the setting of initial disease staging; its utility for guiding management in the setting of metastatic disease is less clear. Although the specificity is high, familiarization with potential pitfalls in the interpretation of PSMA-targeted PET, including knowledge of the causes for false-positive and negative examinations, is critical. The aim of this best practice report is to provide an illustrative discussion of the current and evolving clinical indications for PSMA-targeted PET, as well as a review of physiological radiopharmaceutical biodistribution and potential imaging pitfalls.

Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTDs) have provided evidence-based dementia diagnostic and treatment guidelines for Canadian clinicians and researchers. We present the results from the Neuroimaging and Fluid Biomarkers Group of the 5th CCCDTD (CCCDTD5), which addressed topics chosen by the steering committee to reflect advances in the field and build on our previous guidelines. Recommendations on Imaging and Fluid Biomarker Use from this Conference cover a series of different fields. Prior structural imaging recommendations for both computerized tomography (CT) and magnetic resonance imaging (MRI) remain largely unchanged, but MRI is now more central to the evaluation than before, with suggested sequences described here. The use of visual rating scales for both atrophy and white matter anomalies is now included in our recommendations. Molecular imaging with [ 18 F]-fluorodeoxyglucose ([18F]-FDG) Positron Emisson Tomography (PET) or [ 99m Tc]-hexamethylpropyleneamine oxime/ethylene cysteinate dimer ([ 99m Tc]-HMPAO/ECD) Single Photon Emission Tomography (SPECT), should now decidedly favor PET. The value of [ 18 F]-FDG PET in the assessment of neurodegenerative conditions has been established with greater certainty since the previous conference, and it has now been recognized as a useful biomarker to establish the presence of neurodegeneration by a number of professional organizations around the world. Furthermore, the role of amyloid PET has been clarified and our recommendations follow those from other groups in multiple countries. SPECT with [ 123 I]-ioflupane (DaTscan TM ) is now included as a useful study in differentiating Alzheimer's disease (AD) from Lewy body disease. Finally, liquid biomarkers are in a rapid phase of development and, could lead to a revolution in the assessment AD and other neurodegenerative conditions at a reasonable cost. We hope these guidelines will be useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence-based approach to the use of neuroimaging and liquid biomarkers in clinical dementia evaluation and management., Competing Interests: All authors have completed, or have confirmed having read, the ICMJE form on Conflicts of Interest. There is no conflict of interest to report., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

This article is the second part in our machine learning series. Part 1 provided a general overview of machine learning in nuclear medicine. Part 2 focuses on neural networks. We start with an example illustrating how neural networks work and a discussion of potential applications. Recognizing that there is a spectrum of applications, we focus on recent publications in the areas of image reconstruction, low-dose PET, disease detection, and models used for diagnosis and outcome prediction. Finally, since the way machine learning algorithms are reported in the literature is extremely variable, we conclude with a call to arms regarding the need for standardized reporting of design and outcome metrics and we propose a basic checklist our community might follow going forward., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Our purpose was to investigate the effect of the addition of prostate-specific membrane antigen (PSMA)-targeted positron emission tomography/computed tomography (PET/CT) in patients with recurrent prostate cancer post-primary radiation therapy., Methods and Materials: A prospective, multi-institutional clinical trial evaluated 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ( 18 F-DCFPyL) PET/CT restaging in 79 men with recurrent prostate cancer post-primary radiation therapy. We report actual patient management and compare this with proposed management both before and after PSMA-targeted PET/CT., Results: Most patients (59%) had a major change in actual management compared with pre-PET/CT proposed management. The rate of major change was underestimated by immediately post-PET/CT surveys (32%). Eighteen patients with PSMA avidity in the prostate gland suspicious for malignancy had a prostate biopsy. Sensitivity, specificity, and positive predictive values of PSMA uptake in the prostate were 86%, 67%, and 92%, respectively. Thirty percent of patients had directed salvage therapy and 41% underwent systemic therapy. Eleven out of 79 patients (14%) had high-dose-rate brachytherapy alone for local recurrence, and 91% were free of recurrence at a median follow-up of 20 months., Conclusions: Most patients had a major change in actual management compared with pre-PSMA-targeted PET/CT planned management, and this was underestimated by post-PET/CT questionnaires., (© 2020 The Author(s).)

Purpose: The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score., Materials and Methods: Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB., Results: F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score., Conclusions: Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.

The number of cases of dementia has dramatically increased over the last decade. Imaging of the brain with PET has been used for many years, but in the past decade the radiopharmaceuticals and technology available for imaging dementia have vastly improved. In recent years, the U.S. Food and Drug Administration has approved 3 PET radiopharmaceuticals for detecting amyloid in brain, and tau PET radiopharmaceuticals are being investigated in clinical trials for use in dementia imaging. This paper will discuss different forms of dementia that can be imaged with PET, review common radiopharmaceuticals used for imaging dementia, and provide technical recommendations for performing the studies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Radio-recurrent prostate cancer is typically detected by a rising prostate-specific antigen and may reflect local or distant disease. Positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen, such as 18F-DCFPyL have shown promise in restaging men with recurrent disease postprostatectomy but are less well characterized in the setting of radio-recurrent disease., Methods and Materials: A prospective, multi-institutional study was conducted to evaluate the effect of 18F-DCFPyL PET/computed tomography (CT) when added to diagnostic imaging (DI; CT abdomen and pelvis, bone scan, multiparametric magnetic resonance imaging pelvis) for men with radio-recurrent prostate cancer. All men were imaged with DI and subsequently underwent 18F-DCFPyL PET/CT with local and central reads. Tie break reads were performed as required. Management questionnaires were completed after DI and again after 18F-DCFPyL PET/CT. Discordance in patterns of disease detected with 18F-DCFPyL PET/CT versus DI and changes in management were characterized., Results: Seventy-nine men completed the study. Most men had T1 disease (62%) and Gleason score <7 (95%). Median prostate-specific antigen at diagnosis was 7.4 ng/mL and at relapse was 4.8 ng/mL. DI detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 9 out of 79 (11%), distant disease in 12 out of 79 (15%), and no disease in 26 out of 79 (33%). 18F-DCFPyL PET/CT detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 21 out of 79 (27%), distant disease in 24 out of 79 (30%), and no disease in 10 out of 79 (13%). DI identified 8 out of 79 (10%) patients to have oligometastatic disease, compared with 21 out of 79 (27%) with 18F-DCFPyL PET/CT. 18F-DCFPyL PET/CT changed proposed management in 34 out of 79 (43%) patients., Conclusions: 18F-DCFPyL PET/CT identified extraprostatic disease in twice as many men with radio-recurrent prostate cancer compared with DI and detected a site of recurrence in 87% of men compared with 67% with DI. Furthermore, 18F-DCFPyL PET/CT identified potentially actionable disease (prostate only recurrence or oligometastatic disease) in 75% of men and changed proposed management in 43% of men., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification., Methods: The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB., Results: A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees)., Conclusions: Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

The purpose of this study was to assess image quality and quantitative brain PET across a multicenter consortium. Methods: All academic centers and children's hospitals in the Pediatric Brain Tumor Consortium (PBTC) scanned a phantom developed by the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network (SNMMI CTN) for the validation of brain PET studies associated with clinical trials. The phantom comprises 2 separate, fillable sections: a resolution/uniformity section and a clinical simulation section. The resolution/uniformity section is a cylinder 12.7 cm long and 20 cm in diameter; spatial resolution is evaluated subjectively with 2 sets of rods (hot and cold) of varying diameter (4.0, 5.0, 6.25, 7.81, 9.67, and 12.2 mm) and spacing (twice the rod diameter). The clinical simulation section simulates a transverse section of midbrain with ventricles and gray and white matter compartments. If properly filled, hot rods have a 4:1 target-to-background ratio, and gray-to-white matter sections have a 4:1 ratio. Uniformity and image quality were evaluated using the SUV in a small volume of interest as well as subjectively by 2 independent observers using a 4-point scale. Results: Eleven PBTC sites scanned the phantom on 13 PET scanners. The phantom's complexity led to suboptimal filling, particularly of the hot rod section, in 5 sites. The SUV in the uniformity section was within 10% of unity on only 5 of 13 scanners, although 12 of 13 were subjectively judged to have very good to excellent uniformity. Four of 6 hot rods were discernable by all 13 scanners, whereas 3 of 6 cold rods were discernable by only 5 scanners. Four of 13 scanners had a gray-to-white matter ratio between 3.0 and 5.0 (4.0 is truth); however, 11 of 13 scanners were subjectively judged to have very good or excellent image quality. Conclusion: Eleven sites were able to image a powerful phantom developed by the SNMMI CTN that evaluated image uniformity, spatial resolution, and image quality of brain PET. There was considerable variation in PET data across the PBTC sites, possibly resulting from variations in scanning across the sites due to challenges in filling the phantom., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

This article, the first in a 2-part series, provides an introduction to machine learning (ML) in a nuclear medicine context. This part addresses the history of ML and describes common algorithms, with illustrations of when they can be helpful in nuclear medicine. Part 2 focuses on current contributions of ML to our field, addresses future expectations and limitations, and provides a critical appraisal of what ML can and cannot do., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

There are recent advances, namely, a standardized method for reporting therapy response (Hopkins criteria), a multicenter prospective cohort study with excellent negative predictive value of F-FDG PET/CT for N0 clinical neck, a phase III multicenter randomized controlled study establishing the value of a negative posttherapy F-FDG PET/CT for patient management, a phase II randomized controlled study demonstrating radiation dose reduction strategies for human papilloma virus-related disease, and Food and Drug Administration approval of nivolumab for treatment of recurrent head and neck squamous cell carcinoma.

In recent years, several new radiotracers and radionuclide therapies have been developed. There is a renaissance in nuclear medicine and molecular imaging today, for example, in terms of the ability to image and treat neuroendocrine and prostate malignancies. In order to be able to bring a new drug product from bench to bedside and assist patients, while also ensuring patient safety, stringent regulations must be met. However, differences in regulatory requirements, often based on jurisdictional politics rather than scientific evidence, can hinder global co-operation, increase expense, and slow progress. In an effort to rise above these differences, nuclear medicine advocacy organizations, regulators, and international agencies have begun to identify commonalities in the regulations to achieve harmonization. Indeed, a more streamlined approach to radiopharmaceutical drug development across jurisdictions could be achieved through establishing harmonized requirements for pre-clinical studies and manufacturing standards. This paper provides an educational overview of the regulatory and submission requirements governing investigational radiopharmaceuticals for first-in-human radiopharmaceuticals across the European and North American continents. It is hoped that through ongoing collaboration, regulatory reform and harmonization can become a reality and speed access to the most up-to-date evidence-based patient care for all., (Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objective: In this article, we review the literature on PET/CT in the management of dementia, present evidence for best clinical practices, and discuss recent advances in the field., Conclusion: Standard-of-care imaging for dementia includes CT and MRI, primarily for excluding vascular lesions or masses, detecting atrophy, and monitoring disease severity. PET/CT is a powerful functional modality that can differentiate dementia types and influence management. Fluorine-18-FDG PET/CT reveals the spatial pattern of glucose metabolism in the brain. More recently, radiotracers for PET have been developed that bind to amyloid protein, tau protein, and neuroinflammatory markers.

Competing Interests: Competing interests: None declared.

Background: Bone health is a significant concern in men with prostate cancer., Purpose: To evaluate the effectiveness of drug, supplement, and lifestyle interventions aimed at preventing fracture, improving bone mineral density (BMD), or preventing or delaying osteoporosis in men with nonmetastatic prostate cancer., Data Sources: Ovid MEDLINE (1946 to 19 January 2017), EMBASE (1980 to 18 January 2017), and the Cochrane Database of Systematic Reviews (19 January 2017)., Study Selection: Randomized trials and systematic reviews of trials that were published in English; involved men with nonmetastatic prostate cancer; and compared bone-targeted therapies with placebo, usual care, or other active treatments., Data Extraction: Two reviewers independently extracted study characteristics and assessed study risk of bias for each outcome., Data Synthesis: Two systematic reviews and 28 reports of 27 trials met inclusion criteria. All trials focused on men with nonmetastatic prostate cancer who were initiating or continuing androgen deprivation therapy (ADT). Bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures. Denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures in 1 high-quality trial. No trials compared calcium or vitamin D versus placebo. Three lifestyle intervention trials did not show a statistically significant difference in change in BMD between exercise and usual care., Limitations: Most trials were of moderate quality. Only 2 randomized controlled trials were designed to examine fracture outcomes. Potential harms of treatments were not evaluated., Conclusion: Both bisphosphonates and denosumab improve BMD in men with nonmetastatic prostate cancer who are receiving ADT. Denosumab also reduces risk for radiographic vertebral fractures, based on 1 trial. More trials studying fracture outcomes are needed in this population., Primary Funding Source: Program in Evidence-Based Care.

Purpose: To improve the performance for localizing epileptic foci, we have developed a joint ictal/inter-ictal SPECT reconstruction method in which ictal and inter-ictal SPECT projections are simultaneously reconstructed to obtain the differential image., Methods: We have developed a SPECT reconstruction method that jointly reconstructs ictal and inter-ictal SPECT projection data. We performed both phantom and patient studies to evaluate the performance of our joint method for epileptic foci localization as compared with the conventional subtraction method in which the differential image is obtained by subtracting the inter-ictal image from the co-registered ictal image. Two low-noise SPECT projection datasets were acquired using 99m Tc and a Hoffman head phantom at two different positions and orientations. At one of the two phantom locations, a low-noise dataset was also acquired using a 99m Tc-filled 3.3-cm sphere with a cold attenuation background identical to the Hoffman phantom. These three datasets were combined and scaled to mimic low-noise clinical ictal (three different lesion-to-background contrast levels: 1.25, 1.55, and 1.70) and inter-ictal scans. For each low-noise dataset, 25 noise realizations were generated by adding Poisson noise to the projections. The mean and standard deviation (SD) of lesion contrast in the differential images were computed using both the conventional subtraction and our joint methods. We also applied both methods to the 35 epileptic patient datasets. Each differential image was presented to two nuclear medicine physicians to localize a lesion and specify a confidence level. The readers' data were analyzed to obtain the localized-response receiver operating characteristic (LROC) curves for both the subtraction and joint methods., Results: For the phantom study, the difference between the mean lesion contrast in the differential images obtained using the conventional subtraction versus our joint method decreases as the iteration number increases. Compared with the conventional subtraction approach, the SD reduction of lesion contrast at the 10 th iteration using our joint method ranges from 54.7% to 68.2% (P < 0.0005), and 33.8% to 47.9% (P < 0.05) for 2 and 4 million total inter-ictal counts, respectively. In the patient study, our joint method increases the area under LROC from 0.24 to 0.34 and from 0.15 to 0.20 for the first and second reader, respectively. We have demonstrated improved performance of our method as compared to the standard subtraction method currently used in clinical practice., Conclusion: The proposed joint ictal/inter-ictal reconstruction method yields better performance for epileptic foci localization than the conventional subtraction method., (© 2017 American Association of Physicists in Medicine.)

Interim and end-of-treatment PET/CT have become central to the evaluation of Hodgkin and non-Hodgkin lymphoma. This review article seeks to aid clinical decision making by providing an overview of available data on the diagnostic and prognostic value of PET/CT imaging for response assessment and pretransplant evaluation in lymphoma. The relative strengths and limitations of these techniques in various disease subtypes and clinical scenarios are explored, along with their current standards for reporting and latest developments. Particular attention is given to response-adapted therapy, which is emerging as a cornerstone of clinical management., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

The effectiveness of cancer therapy, both in individual patients and across populations, requires a systematic and reproducible method for evaluating response to treatment. Early efforts to meet this need resulted in the creation of numerous guidelines for quantifying posttherapy changes in disease extent, both anatomically and metabolically. Over the past few years, criteria for disease response classification have been developed for specific cancer histologies. To date, the spectrum of disease broadly referred to as lymphoma is perhaps the most common for which disease response classification is used. This review article provides an overview of the existing response assessment criteria for lymphoma and highlights their respective methodologies and validities. Concerns over the technical complexity and arbitrary thresholds of many of these criteria, which have impeded the long-standing endeavor of standardizing response assessment, are also discussed., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

In recent years, there has been a proliferation in the development of targeted radionuclide cancer therapy. It is now possible to use baseline clinical and imaging assessments to determine the most effective therapy and to tailor this therapy during the course of treatment based on radiation dosimetry and tumor response. Although this personalized approach to medicine has the advantage of maximizing therapeutic effect while limiting toxicity, it can be challenging to implement and expensive. Further, in order to use targeted radionuclide therapy effectively, there is a need for multidisciplinary awareness, education, and collaboration across the scientific, industrial, and medical communities. Even more important, there is a growing understanding that combining radiopharmaceuticals with conventional treatment such as chemotherapy and external beam radiotherapy may limit patient morbidity while improving survival. Developments in radiopharmaceuticals as biomarkers capable of predicting therapeutic response and targeting disease are playing a central role in medical research. Adoption of a practical approach to manufacturing and delivering radiopharmaceuticals, assessing patient eligibility, optimizing post-therapy follow-up, and addressing reimbursement issues will be essential for their success.

The prognosis of men with metastatic, castration-sensitive prostate cancer (CSPC) depends on both the distribution and extent of metastases, among other things. Patients with low-volume or oligometastatic disease have improved survival compared with those with high-volume metastases. While chemohormonal therapy is the new standard of care for men with high-volume metastatic CSPC, stereotactic ablative radiotherapy (SABR) is emerging as a promising treatment option with low toxicity for the management of oligometastatic CSPC. Our review summarizes the current evidence on the role of SABR in oligometastatic prostate cancer. SABR shows control rates of metastases ranging from 88% to 100% at 6 months to 3 years, and progression-free survival commonly reported as >50% for the first 12 months. In addition, SABR may allow androgen-deprivation therapy to be delayed by more than 2 years in selected patients, minimizing the chronic side effects associated with such therapy. However, much still needs to be learned before SABR can be implemented as standard treatment for oligometastatic prostate cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To determine if the minimum administered radiopharmaceutical activity for hepatobiliary scintigraphy can be reduced while preserving diagnostic image quality using enhanced planar processing (EPP)., Methods: A total of 40 infants between 10 and 270 days old (body mass 2.2 - 6.5 kg) had hepatobiliary scintigraphy during the period 2004 - 2010 following the intravenous administration of either (99m)Tc-mebrofenin (18 patients) or (99m)Tc-disofenin (22 patients). Due to the small size of these patients, they all received the minimum administered activity of 18.5 MBq consistent with the North American Consensus Guidelines. Six nuclear medicine physicians subjectively graded the acceptability of the image quality for clinical interpretation using a four-point scale (not acceptable, fair, good, excellent). Each physician independently graded seven image sets including the original study (full activity) and simulated reduced activity studies using binomial subsampling (50% of full activity, 25% of full activity and activity reduced by weight), with and without EPP., Results: For full-activity studies, 98% were deemed acceptable by the six physicians for clinical interpretation. The percentages of acceptable 50% reduced activity studies with and without EPP were not significantly different from the percentage of acceptable full-activity studies (P = 0.193 and P = 0.998, respectively). The percentage of acceptable 25% reduced activity studies without EPP was significantly different from the percentage of acceptable full-activity studies (P < 0.001); however, this difference vanished when EPP was applied (P = 0.482). The activity reduced by weight ranged from 1.85 to 4.81 MBq (10% to 26% of full dose) and the percentages of acceptable studies with and without EPP were significantly different from the percentage of acceptable full-activity studies (P < 0.001 and P = 0.02, respectively)., Conclusion: Clinically interpretable hepatobiliary scintigraphy images can be obtained in infants when the minimum administered activity is substantially reduced. Without EPP, clinically acceptable images may be produced with a reduction of 50%, and with EPP, a reduction of 75% or more may be possible.

Background: In patients with metastatic melanoma and KIT amplifications and/or mutations, therapy with imatinib mesylate may prolong survival. 18F-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT may be used to assess metabolic response. We investigated associations of metabolic response, mutational status, progression-free survival and overall survival in this population., Methods: Baseline and 4-week follow-up 18F-FDG-PET/CT were evaluated in 17 patients with metastatic melanoma and KIT amplifications and/or mutations treated with imatinib in a multicenter phase II clinical trial. The maximum standardized uptake values (SUVmax) were measured in up to 10 lesions on each scan. Metabolic response was classified using modified EORTC criteria. Each patient had a diagnostic CT or MR at baseline, after 6 weeks of therapy and then at intervals of 2 months and anatomic response was classified using RECIST 1.0. Median follow-up was 9.8 months., Results: Partial metabolic response (PMR), stable metabolic disease (SMD) and progressive metabolic disease (PMD) was seen in 5 (29%), 5 (29%), and 7 (41%) patients respectively. Five patients (29%) had a KIT mutation in exon 11, four of whom (80%) had PMR while 1 (20%) had SMD. Twelve patients (71%) did not have a KIT mutation in exon 11, and only 1 (8%) had PMR, 4 (33%) had SMD and 7 (58%) had PMD. There was agreement of metabolic and anatomic classification in 12 of 17 patients (71%). Four of 17 patients (24%) had PR on both metabolic and anatomic imaging and all had a KIT mutation in exon 11. Survival of patients with PMD was lower than with SMD or PMR., Conclusions: Metabolic response by 18F-FDG-PET/CT is associated with mutational status in metastatic melanoma patients treated with imatinib. 18F-FDG-PET/CT may be a predictor of outcome, although a larger study is needed to verify this., Clinical Trial Registration: NCT00424515.

Unlabelled: The purpose of this study was to describe (18)F-FDG uptake across a spectrum of pediatric brain tumors and correlate (18)F-FDG PET with MR imaging variables, progression-free survival (PFS), and overall survival (OS)., Methods: A retrospective analysis was conducted of children enrolled in phase I/II clinical trials through the Pediatric Brain Tumor Consortium from August 2000 to June 2010. PET variables were summarized within diagnostic categories using descriptive statistics. Associations of PET with MR imaging variables and PFS and OS by tumor types were evaluated., Results: Baseline (18)F-FDG PET was available in 203 children; 66 had newly diagnosed brain tumors, and 137 had recurrent/refractory brain tumors before enrolling in a Pediatric Brain Tumor Consortium trial. MR imaging was performed within 2 wk of PET and before therapy in all cases. The (18)F-FDG uptake pattern and MR imaging contrast enhancement (CE) varied by tumor type. On average, glioblastoma multiforme and medulloblastoma had uniform, intense uptake throughout the tumor, whereas brain stem gliomas (BSGs) had low uptake in less than 50% of the tumor and ependymoma had low uptake throughout the tumor. For newly diagnosed BSG, correlation of (18)F-FDG uptake with CE portended reduced OS (P = 0.032); in refractory/recurrent BSG, lack of correlation between (18)F-FDG uptake and CE suggested decreased PFS (P = 0.023). In newly diagnosed BSG for which more than 50% of the tumor had (18)F-FDG uptake, there was a suggestion of lower apparent diffusion coefficient (P = 0.061) and decreased PFS (P = 0.065)., Conclusion: (18)F-FDG PET and MR imaging showed a spectrum of patterns depending on tumor type. In newly diagnosed BSG, the correlation of (18)F-FDG uptake and CE suggested decreased OS, likely related to more aggressive disease. When more than 50% of the tumor had (18)F-FDG uptake, the apparent diffusion coefficient was lower, consistent with increased cellularity. In refractory/recurrent BSG, poor correlation between (18)F-FDG uptake and CE was associated with decreased PFS, which may reflect concurrent tissue breakdown at sites of treated disease and development of new sites of (18)F-FDG-avid malignancy., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The increasing use of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in oncology has led to: improved sensitivity and specificity in detecting localized and metastatic disease, increased ability to target biopsies to the site of most aggressive disease, and development of a noninvasive biomarker to assess prognosis and effects of therapy. However, for correct interpretation of FDG-PET/CT studies, an understanding of both normal and abnormal imaging appearances commonly encountered in oncology patients is important. This article discusses commonly seen normal variations and benign findings on FDG-PET/CT of the abdomen., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Imaging plays a central role in the detection, diagnosis, staging, and follow-up of prostate carcinoma. This article discusses the role of multiple imaging modalities in the diagnosis and staging of prostate cancer, with attention to imaging features of localized and metastatic disease, imaging adjuncts to improve prostate biopsy, and potential imaging biomarkers. In addition, the role of imaging in the management of prostate cancer, with emphasis on surveillance, evaluation of response to new therapies, and detection of recurrent disease is described. Lastly, future directions in prostate cancer imaging are presented., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The role of FDG PET/CT in anal cancer is becoming increasingly important. At the time of initial staging, FDG PET/CT can detect the primary site of disease more frequently than CT, is sensitive for nodal and metastatic spread and alters staging in a significant number of patients. Indeed, the NCCN guidelines for anal cancer published in April 2012 recommend FDG PET/CT for therapy planning. Metabolic activity of primary anal cancer at presentation is a potential biomarker for predicting prognosis, treatment response and survival. More intensely FDG-avid primary malignancy is associated with a higher incidence of disease spread. Metabolic response following chemoradiotherapy is associated with improved survival. The aim of this paper is to provide an up-to-date pictorial review of FDG PET/CT in anal cancer at the time of staging and to illustrate its utility for determining response to therapy and detecting recurrent disease.

Objective: The purpose of this article is to describe the advantages and diagnostic and prognostic implications of imaging in the management of vulvar carcinoma., Conclusion: As the treatment of vulvar carcinoma evolves to tailored surgery and chemoradiation therapy to reduce morbidity, the importance of pretreatment assessment of vulvar carcinoma increases. Advances in imaging, such as pelvic MRI and PET, add to the benefits of clinical evaluation in pretreatment planning, assessment of response to chemoradiation therapy, and posttreatment surveillance.

Objective: Rhabdomyosarcomas are rare and aggressive soft-tissue sarcomas in adults. The purpose of this article is to describe the imaging features of primary and secondary adult rhabdomyosarcomas utilizing MRI, CT, and (18)F-FDG PET/CT., Conclusion: MRI is the imaging technique of choice for the evaluation of primary rhabdomyosarcoma involving most body sites (extremity, pelvis, head, and neck), with the added advantages of diffusion-weighted imaging and whole-body MRI for staging. CT and FDG PET/CT play major roles in the evaluation of metastatic disease. Because the imaging features of adult rhabdomyosarcoma are nonspecific, other parameters, such as clinical findings, age, site, lymphadenopathy, and metastatic disease, should be combined to narrow the differential diagnosis.

Objective: The purpose of this study was to evaluate the utilization and role of MRI in the management of myeloid sarcoma in adults., Materials and Methods: A retrospective study of 69 patients with pathologically proven myeloid sarcoma included 25 patients (16 men, nine women; mean age, 55 years; range, 22-78 years) who underwent pretreatment MRI at our institution from January 2001 to October 2011. A total of 71 MRI examinations were evaluated by two radiologists in consensus., Results: A total of 41 sites of involvement of myeloid sarcoma were noted, most commonly bone (13/25, 52%), muscle (7/25, 28%), CNS (6/25, 24%), and head and neck (6/25, 24%). Nineteen sites were noted on MR images obtained for evaluation of a new sign or symptom, most commonly musculoskeletal (11 sites) and CNS (six sites). Fifteen sites were noted on MR images obtained for further evaluation of a previously detected abnormality, most commonly in the abdomen and pelvis (seven sites). Seven lesions were incidentally found on MR images obtained for other myeloid sarcoma-related indications, most commonly in the head and neck (three lesions) and musculoskeletal system (three lesions). The mean size of measurable lesions was 5.6 cm (range, 1-20 cm). Compared with muscle, the lesions were isointense (31/41, 75.6%) or hypointense (10/41, 24.4%) on T1-weighted images and mildly hyperintense (39/41, 95.1%) on T2-weighted images and had homogeneous enhancement (29/38, 76.3%)., Conclusion: In our experience, MRI was most often used for evaluation of bone, muscle, the CNS, and the head and neck region. MRI is useful for evaluation of new musculoskeletal and CNS findings and for further evaluation of known abdominopelvic masses. Incidental findings are often musculoskeletal or in the soft tissues of the head and neck.

Objective: PET/CT with (18)F-FDG shows metabolically active disease and is widely used for the diagnosis and follow-up of patients with cancer. Nonmetabolically active renal pathology may be missed without close attention to the CT portion of the study, whereas metabolically active pathology may be missed on PET because of physiologic tracer excretion in the kidneys. This article illustrates primary lesions of the kidney on FDG PET/CT with emphasis on key anatomic features and the appearance of tracer uptake., Conclusion: Close attention to both the FDG PET and CT portions of the study is essential to interpret renal pathology correctly on FDG PET/CT examinations.

Objective: PET/CT with (18)F-FDG is a powerful tool to evaluate patients with hematologic malignancy or to assess the burden of metastatic disease from solid tumors. Metabolically active renal pathology associated with lymphoma, leukemia, or metastatic disease can be missed without close attention to both the PET and CT portions of the study because of physiologic FDG excretion in the kidneys. This article illustrates the appearance of tracer uptake and the key anatomic features of lymphoma, leukemia, and metastatic disease involving the kidney on FDG PET/CT., Conclusion: Close attention to both the FDG PET and CT portions of an FDG PET/CT study is essential to evaluate the kidneys in oncology patients.