Nuclear Medicine Imaging Tools in Fever of Unknown Origin: Time for a Revisit and Appropriate Use Criteria.

Fever of unknown origin (FUO) is a clinical conundrum for patients and clinicians alike, and imaging studies are often performed as part of the diagnostic workup of these patients. Recently, the Society of Nuclear Medicine and Molecular Imaging convened and approved a guideline on the use of nuclear medicine tools for FUO. The guidelines support the use of 2-18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in adults and children with FUO. 18F-FDG PET/CT allows detection and localization of foci of hypermetabolic lesions with high sensitivity because of the 18F-FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. Clinicians should consider and insurers should cover 18F-FDG PET/CT when evaluating patients with FUO, particularly when other clinical clues and preliminary studies are unrevealing.

Combining Nuclear Medicine With Other Modalities: Future Prospect for Multimodality Imaging.

This meeting report summarizes a consultants meeting that was held at International Atomic Energy Agency Headquarters, Vienna, in July 2022 to provide an update on the development of multimodality imaging by combining nuclear medicine imaging agents with other nonradioactive molecular probes and/or biomedical imaging techniques.

Implementation of PSMA PET/CT and alignment of ordering to SNMMI appropriate use criteria in a large network system.

INTRODUCTION: The Society of Nuclear Medicine and Molecular Imaging (SNMMI) provides appropriate use criteria (AUC) for prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) which include guidance on imaging in newly diagnosed prostate cancer and in patients with biochemically recurrent (BCR) disease. This study aims to examine trends in PSMA implementation and the prevalence and outcomes of scans ordered in scenarios deemed rarely appropriate or not meeting SNMMI AUC. METHODS: We retrospectively identified patients who were diagnosed with presumptive National Comprehensive Cancer Network unfavorable intermediate, high, or very high risk prostate cancer, patients who underwent staging for BCR, and all patients staged with PSMA between July 2021 and March 2023. Positivity was validated by adherence to a predetermined reference standard. RESULTS: The frequency of PSMA use increased in initial staging from 24% to 80% and work-up of BCR from 91% to 99% over our study period. In addition, 5% (17/340) of PSMA scans ordered for initial staging did not meet AUC and 3% (15/557) of posttreatment scans were deemed rarely appropriate. Initial staging orders not meeting SNMMI AUC resulted in no positivity (0/17), while rarely appropriate posttreatment scans were falsely positive in 75% (3/4) of cases. Urologists (53%, 17/32) comprised the largest ordering specialty in rarely appropriate use. CONCLUSION: The frequency of PSMA use rose across the study period. A significant minority of patients received PSMA PET/CT in rarely appropriate scenarios yielding no positivity in initial staging and significant false positivity post-therapy. Further education of providers and electronic medical record-based interventions could help limit the rarely appropriate use of PET imaging.

EANM guidance document: dosimetry for first-in-human studies and early phase clinical trials.

The numbers of diagnostic and therapeutic nuclear medicine agents under investigation are rapidly increasing. Both novel emitters and novel carrier molecules require careful selection of measurement procedures. This document provides guidance relevant to dosimetry for first-in human and early phase clinical trials of such novel agents. The guideline includes a short introduction to different emitters and carrier molecules, followed by recommendations on the methods for activity measurement, pharmacokinetic analyses, as well as absorbed dose calculations and uncertainty analyses. The optimal use of preclinical information and studies involving diagnostic analogues is discussed. Good practice reporting is emphasised, and relevant dosimetry parameters and method descriptions to be included are listed. Three examples of first-in-human dosimetry studies, both for diagnostic tracers and radionuclide therapies, are given.

Nuclear medicine and pediatric nephro-urology: a long-lasting successful partnership.

Congenital anomalies of the kidney and urinary tract, as well as urinary infections, are very frequent in children. After the clinical and laboratory evaluation, the first imaging procedure to be done is a renal and bladder ultrasound, but afterwards, a main contribution comes from nuclear medicine. Through minimally invasive and sedation-free procedures, nuclear medicine allows the evaluation of the functional anatomy of the urinary tract, and the quantification of renal function and drainage. If pediatric dosage cards provided by scientific societies are used, radiation exposure can also be low. In the pediatric conditions previously mentioned, nuclear medicine is used both for initial diagnosis and follow-up, mostly in cases of suspicion of ureteropelvic or ureterovesical junction syndromes, as well as vesicoureteral reflux or renal scars of febrile infectious episodes. Pediatric nephro-urology constitutes a significant workload of pediatric nuclear medicine departments. The following paragraphs are a revision of the renal radiopharmaceuticals, as well as the nuclear nephro-urology procedures - dynamic and static renal scintigraphy, and direct and indirect radionuclide cystography. A summary of the techniques, main indications, interpretation criteria and pitfalls will be provided. Some future directions for the field are also pointed out, among which the most relevant is the need for nuclear medicine professionals to use standardized protocols and integrate multidisciplinary teams with other pediatric and adult health professionals that manage these life-long pediatric pathologies, which are recognized as an important cause of adult chronic kidney disease.

Targeted Molecular Imaging and Therapy Based on Nuclear and Optical Technologies.

Both nuclear and optical imaging are used for in vivo molecular imaging. Nuclear imaging displays superior quantitativity, and it permits imaging in deep tissues. Thus, this method is widely used clinically. Conversely, because of the low permeability of visible to near-IR light in living animals, it is difficult to visualize deep tissues via optical imaging. However, the light at these wavelengths has no ionizing effect, and it can be used without any restrictions in terms of location. Furthermore, optical signals can be controlled in vivo to accomplish target-specific imaging. Nuclear medicine and phototherapy have also evolved to permit targeted-specific imaging. In targeted nuclear therapy, beta emitters are conventionally used, but alpha emitters have received significant attention recently. Concerning phototherapy, photoimmunotherapy with near-IR light was approved in Japan in 2020. In this article, target-specific imaging and molecular targeted therapy utilizing nuclear medicine and optical technologies are discussed.

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues.

Scandium (Sc) isotopes have recently attracted significant attention in the search for new radionuclides with potential uses in personalized medicine, especially in the treatment of specific cancer patient categories. In particular, Sc-43 and Sc-44, as positron emitters with a satisfactory half-life (3.9 and 4.0 h, respectively), are ideal for cancer diagnosis via Positron Emission Tomography (PET). On the other hand, Sc-47, as an emitter of beta particles and low gamma radiation, may be used as a therapeutic radionuclide, which also allows Single-Photon Emission Computed Tomography (SPECT) imaging. As these scandium isotopes follow the same biological pathway and chemical reactivity, they appear to fit perfectly into the "theranostic pair" concept. A step-by-step description, initiating from the moment of scandium isotope production and leading up to their preclinical and clinical trial applications, is presented. Recent developments related to the nuclear reactions selected and employed to produce the radionuclides Sc-43, Sc-44, and Sc-47, the chemical processing of these isotopes and the main target recovery methods are also included. Furthermore, the radiolabeling of the leading chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and its structural analogues with scandium is also discussed and the advantages and disadvantages of scandium complexation are evaluated. Finally, a review of the preclinical studies and clinical trials involving scandium, as well as future challenges for its clinical uses and applications, are presented.

Radiolabeled Probes from Derivatives of Natural Compounds Used in Nuclear Medicine.

Natural compounds are important precursors for the synthesis of new drugs. The development of novel molecules that are useful for various diseases is the main goal of researchers, especially for the diagnosis and treatment of many diseases. Some pathologies need to be treated with radiopharmaceuticals, and, for this reason, radiopharmaceuticals that use the radiolabeling of natural derivates molecules are arousing more and more interest. Radiopharmaceuticals can be used for both diagnostic and therapeutic purposes depending on the radionuclide. ß+- and gamma-emitting radionuclides are used for diagnostic use for PET or SPECT imaging techniques, while α- and ß--emitting radionuclides are used for in metabolic radiotherapy. Based on these assumptions, the purpose of this review is to highlight the studies carried out in the last ten years, to search for potentially useful radiopharmaceuticals for nuclear medicine that use molecules of natural origin as lead structures. In this context, the main radiolabeled compounds containing natural products as scaffolds are analyzed, in particular curcumin, stilbene, chalcone, and benzofuran. Studies on structural and chemical modifications are emphasized in order to obtain a collection of potential radiopharmaceuticals that exploit the biological properties of molecules of natural origin. The radionuclides used to label these compounds are 68Ga, 44Sc, 18F, 64Cu, 99mTc, and 125I for diagnostic imaging.

A Brief History of Nuclear Medicine Imaging of Infection.

For nearly 50 years, nuclear medicine has played an important role in the diagnosis of infection. Gallium citrate Ga 67 was one of the first, if not the first, radionuclide used for this purpose. Unfavorable imaging characteristics, a lack of specificity, and the long interval (2-3 days) between administration and imaging spurred the search for alternatives. At the present time, gallium 67 citrate is used primarily for differentiating acute tubular necrosis from interstitial nephritis and as an alternative for indications including sarcoid, spondylodiscitis, and fever of unknown origin, when 18F-fluorodeoxyglucose (18F-FDG) is not available. The approval, in the mid-1980s, of techniques for in vitro labeling of leukocytes with indium-111 and technetium-99m that subsequently migrate to foci of infection was a significant advance in nuclear medicine imaging of infection and labeled leukocyte imaging still plays an important role in imaging of infection. There are significant disadvantages to in vitro labeled leukocyte imaging. Unfortunately, efforts devoted to developing in vivo leukocyte labeling methods have met with only limited success. Over the past 20 years 18F-FDG has established itself as a valuable imaging agent for musculoskeletal and cardiovascular infections, as well as sarcoidosis and fever of unknown origin. As useful as these agents are, their uptake is based on the host response to infection, not infection itself. Previous attempts at developing infection-specific agents, including radiolabeled antibiotics and vitamins, were limited by poor results and/or lack of availability, so investigators continue to focus on developing infection-specific nuclear medicine imaging agents.

Joint EANM/SNMMI guideline on radiomics in nuclear medicine : Jointly supported by the EANM Physics Committee and the SNMMI Physics, Instrumentation and Data Sciences Council.

PURPOSE: The purpose of this guideline is to provide comprehensive information on best practices for robust radiomics analyses for both hand-crafted and deep learning-based approaches. METHODS: In a cooperative effort between the EANM and SNMMI, we agreed upon current best practices and recommendations for relevant aspects of radiomics analyses, including study design, quality assurance, data collection, impact of acquisition and reconstruction, detection and segmentation, feature standardization and implementation, as well as appropriate modelling schemes, model evaluation, and interpretation. We also offer an outlook for future perspectives. CONCLUSION: Radiomics is a very quickly evolving field of research. The present guideline focused on established findings as well as recommendations based on the state of the art. Though this guideline recognizes both hand-crafted and deep learning-based radiomics approaches, it primarily focuses on the former as this field is more mature. This guideline will be updated once more studies and results have contributed to improved consensus regarding the application of deep learning methods for radiomics. Although methodological recommendations in the present document are valid for most medical image modalities, we focus here on nuclear medicine, and specific recommendations when necessary are made for PET/CT, PET/MR, and quantitative SPECT.

The potential of a medium-cost long axial FOV PET system for nuclear medicine departments.

PURPOSE: Total body positron emission tomography (TB-PET) has recently been introduced in nuclear medicine departments. There is a large interest in these systems, but for many centers, the high acquisition cost makes it very difficult to justify their current operational budget. Here, we propose medium-cost long axial FOV scanners as an alternative. METHODS: Several medium-cost long axial FOV designs are described with their advantages and drawbacks. We describe their potential for higher throughput, more cost-effective scanning, a larger group of indications, and novel research opportunities. The wider spread of TB-PET can also lead to the fast introduction of new tracers (at a low dose), new methodologies, and optimized workflows. CONCLUSIONS: A medium-cost TB-PET would be positioned between the current standard PET-CT and the full TB-PET systems in investment but recapitulate most advantages of full TB-PET. These systems could be more easily justified financially in a standard academic or large private nuclear medicine department and still have ample research options.

EANM practice guideline for quantitative SPECT-CT.

PURPOSE: Quantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging together with the concept of theranostics more generally. The aim of this document is to provide guidelines for nuclear medicine departments setting up and developing their quantitative SPECT-CT service with guidance on protocols, harmonisation and clinical use cases. METHODS: These practice guidelines were written by members of the European Association of Nuclear Medicine Physics, Dosimetry, Oncology and Bone committees representing the current major stakeholders in Quantitative SPECT-CT. The guidelines have also been reviewed and approved by all EANM committees and have been endorsed by the European Association of Nuclear Medicine. CONCLUSION: The present practice guidelines will help practitioners, scientists and researchers perform high-quality quantitative SPECT-CT and will provide a framework for the continuing development of quantitative SPECT-CT as an established modality.

Hot spot imaging in cardiovascular diseases: an information statement from SNMMI, ASNC, and EANM.

This information statement from the Society of Nuclear Medicine and Molecular Imaging, American Society of Nuclear Cardiology, and European Association of Nuclear Medicine describes the performance, interpretation, and reporting of hot spot imaging in nuclear cardiology. The field of nuclear cardiology has historically focused on cold spot imaging for the interpretation of myocardial ischemia and infarction. Hot spot imaging has been an important part of nuclear medicine, particularly for oncology or infection indications, and the use of hot spot imaging in nuclear cardiology continues to expand. This document focuses on image acquisition and processing, methods of quantification, indications, protocols, and reporting of hot spot imaging. Indications discussed include myocardial viability, myocardial inflammation, device or valve infection, large vessel vasculitis, valve calcification and vulnerable plaques, and cardiac amyloidosis. This document contextualizes the foundations of image quantification and highlights reporting in each indication for the cardiac nuclear imager.

Synthesis of 177Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics.

Self-assembled supramolecular coordination complexes (SCCs) hold promise for biomedical applications in cancer therapy, although their potential in the field of nuclear medicine is still substantially unexplored. Therefore, in this study an exo-functionalized cationic [Pd2L2]4+ metallacycle (L = 3,5-bis(3-ethynylpyridine)phenyl), targeted to the somatostatin-2 receptor (sst2R) and featuring the DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) in order to bind the ß-- and γ-emitter lutetium-177, was synthesized by self-assembly following ligand synthesis via standard solid-phase peptide synthesis (SPPS). This metallacycle was then characterized by reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionization mass spectrometry (ESI-MS), and 1H and 1H-DOSY NMR (DOSY = diffusion-ordered spectroscopy). A procedure for the radiolabeling of the metallacycle with 177Lu was also optimized. The resulting [nat/177Lu]Lu-DOTA-metallacycle, termed [nat/177Lu]Lu-Cy, was evaluated concerning its stability and in vitro properties. The compound was more lipophilic compared to the reference [177Lu]Lu-DOTA-TATE (logPOct/H2O = -0.85 ± 0.10 versus -3.67 ± 0.04, respectively). While [natLu]Lu-Cy revealed low stability in a DMEM/F12 GlutaMax medium, it demonstrated good stability in other aqueous media as well as in DMSO. A high sst2R binding affinity (expressed as IC50) was determined in CHOsst2 cells (Chinese hamster ovary cells that were stably transfected with human sst2R). Moreover, the metallacycle exhibited high human serum albumin binding, as assessed by high-performance affinity chromatography (HPAC), and moderate stability in human serum compared to [177Lu]Lu-DOTA-TATE (TATE = (Tyr3)-octreotate). In order to improve stability, a heteroleptic approach was used to develop a less sterically hindered cage-like SCC that is potentially endowed with host-guest chemistry capability, which has been preliminarily characterized by RP-HPLC and ESI-MS. Overall, our initial results encourage future studies on sst2R-directed SCCs and have led to new insights into the chemistry of ss2R-directed SCCs for radiopharmaceutical applications.

Rhenium Radioisotopes for Medicine, a Focus on Production and Applications.

In recent decades, the use of alpha; pure beta; or beta/gamma emitters in oncology, endocrinology, and interventional cardiology rheumatology, has proved to be an important alternative to the most common therapeutic regimens. Among radionuclides used for therapy in nuclear medicine, two rhenium radioisotopes are of particular relevance: rhenium-186 and rhenium-188. The first is routinely produced in nuclear reactors by direct neutron activation of rhenium-186 via 185Re(n,γ)186Re nuclear reaction. Rhenium-188 is produced by the decay of the parent tungsten-188. Separation of rhenium-188 is mainly performed using a chromatographic 188W/188Re generator in which tungsten-188 is adsorbed on the alumina column, similar to the 99Mo/99mTc generator system, and the radionuclide eluted in saline solution. The application of rhenium-186 and rhenium-188 depends on their specific activity. Rhenium-186 is produced in low specific activity and is mainly used for labeling particles or diphosphonates for bone pain palliation. Whereas, rhenium-188 of high specific activity can be used for labeling peptides or bioactive molecules. One of the advantages of rhenium is its chemical similarity with technetium. So, diagnostic technetium analogs labeled with radiorhenium can be developed for therapeutic applications. Clinical trials promoting the use of 186/188Re-radiopharmaceuticals is, in particular, are discussed.

Perspectives of Methotrexate-Based Radioagents for Application in Nuclear Medicine.

Methotrexate is a gold standard among disease modifying antirheumatic drugs and is also extensively used clinically in combination with oncological therapies. Thus, it is not surprising that nuclear medicine found an interest in methotrexate in the search for diagnostic and therapeutic solutions. Numerous folate-related radiopharmaceuticals have been proposed for nuclear medicine purposes; however, methotrexate radioagents represent only a minority. This imbalance results from the fact that methotrexate has significantly weaker affinity for folate receptors than folic acid. Nevertheless, radiolabeled methotrexate agents utilized as a tool for early detection and imaging of inflammation in rheumatoid arthritis patients gave promising results. Similarly, the use of multimodal MTX-release nanosystems may find potential applications in radiosynovectomy and theranostic approaches in folate receptor positive cancers.

Theranostic Advances in Breast Cancer in Nuclear Medicine.

The implication of 'theranostic' refers to targeting an identical receptor for diagnostic and therapeutic purposes, by the same radioligand, simultaneously or separately. In regard to extensive efforts, many considerable theranostic tracers have been developed in recent years. Emerging evidence strongly demonstrates the tendency of nuclear medicine towards therapies based on a diagnosis. This review is focused on the examples of targeted radiopharmaceuticals for the imaging and therapy of breast cancer.

Bioconjugates of Chelators with Peptides and Proteins in Nuclear Medicine: Historical Importance, Current Innovations, and Future Challenges.

Molecular radiopharmaceuticals based on bioconjugates of chelators with peptides and proteins have had significant clinical impact in the diagnosis and treatment of several types of cancers. In the 1990s, indium-111 and yttrium-90 labeled chelator-peptide/protein conjugates established the clinical utility of these radiopharmaceuticals for receptor-targeted γ-scintigraphy imaging and systemic radiotherapy. Second-generation bioconjugates based on peptides targeting the somatostatin II receptor and the prostate-specific membrane antigen are now widely used for management of neuroendocrine and prostate cancer, respectively. These bioconjugates are typically radiolabeled with gallium-68 for imaging of target receptor expression with positron emission tomography, and the ß--emitter, lutetium-177, for targeted radiotherapy. Innovations in radioisotope technology and biomolecular therapies are likely to drive the future clinical development of radiopharmaceuticals based on radiometals. New chelator-peptide and chelator-protein bioconjugates will underpin nuclear medicine advances in molecular imaging and radiotherapy.

Nuclear medicine in responding to global pandemic COVID-19-American College of Nuclear Medicine member experience.

In the global pandemic COVID-19, it is important for everyone including nuclear medicine personnel to know how to stop transmission and contain and prevent the spread of COVID-19. Here, we summarize our American College of Nuclear Medicine members' experiences from Wuhan, China; Singapore; and the USA, so to provide advice to the nuclear medicine personnel for their clinical practice and management strategies in responding to COVID-19.

A tale of two technologies: Can nuclear cardiology survive the emergence of cardiac CT the seventeenth annual Mario S. Verani lectureship.

The Mario S. Verani Lectureship has traditionally been an opportunity for presenters to reflect on the state of nuclear cardiology in clinical practice and expound on new innovations in the field. Mario Verani was a visionary who embraced change and, as a cardiologist, sought to define where other cardiac imaging techniques might complement nuclear cardiology for improving patient care. Over the last decade, nuclear cardiology and cardiac computed tomography (CT) have developed in parallel with both expanding beyond the evaluation of coronary artery disease. However, many consider cardiac CT a formidable threat to nuclear cardiology due to pivotal technical innovations and its subsequent exponential growth in recent years. It is only fitting that this year's lectureship explore the relative value of both techniques in evaluating and managing cardiac disease, their relative strengths and weaknesses, and the potential value of combining nuclear cardiology and cardiac CT imaging for enhancing patient management. To Mario, my mentor, colleague for over 20 years and friend, this lectureship is truly in honor and remembrance of you.