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The goal of this guideline/procedure standard is to assist nuclear medicine physicians, other nuclear medicine professionals, oncologists or other medical specialists for recommended use of [F]FDG PET/CT in oncological patients undergoing immunotherapy, with special focus on response assessment in solid tumors. In a cooperative effort between the EANM, the SNMMI and the ANZSNM, clinical indications, recommended imaging procedures and reporting standards have been agreed upon and summarized in this joint guideline/procedure standard. The field of immuno-oncology is rapidly evolving, and this guideline/procedure standard should not be seen as definitive, but rather as a guidance document standardizing the use and interpretation of [F]FDG PET/CT during immunotherapy. Local variations to this guideline should be taken into consideration. The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology and practical application of nuclear medicine. The Australian and New Zealand Society of Nuclear Medicine (ANZSNM), founded in 1969, represents the major professional society fostering the technical and professional development of nuclear medicine practice across Australia and New Zealand. It promotes excellence in the nuclear medicine profession through education, research and a commitment to the highest professional standards. EANM, SNMMI and ANZSNM members are physicians, technologists, physicists and scientists specialized in the research and clinical practice of nuclear medicine. All three societies will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the EANM/SNMMI/ANZSNM, has undergone a thorough consensus process, entailing extensive review. These societies recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents based on current knowledge. They are not intended to be inflexible rules or requirements of practice, nor should they be used to establish a legal standard of care. For these reasons and those set forth below, the EANM, SNMMI and ANZSNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an action differing from what is laid out in the guidelines/procedure standards, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines/procedure standards. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/ guidelines will not ensure a successful outcome. All that should be expected is that practitioners follow a reasonable course of action, based on their level of training, current knowledge, clinical practice guidelines, available resources and the needs/context of the patient being treated. The sole purpose of these guidelines is to assist practitioners in achieving this objective. The present guideline/procedure standard was developed collaboratively by the EANM, the SNMMI and the ANZSNM, with the support of international experts in the field. They summarize also the views of the Oncology and Theranostics and the Inflammation and Infection Committees of the EANM, as well as the procedure standards committee of the SNMMI, and reflect recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin αvβ3 receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin αvβ3 receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin αvβ3 tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (18F,64Cu, and68Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Purpose: [⁶⁸Ga]Ga-PSMA-11 is a promising radiopharmaceutical for detecting tumour lesions in prostate cancer, but knowledge of the pharmacokinetics is limited. Dynamic PET-CT was performed to investigate the tumour detection and differences in temporal distribution, as well as in kinetic modelling of [⁶⁸Ga]Ga-PSMA-11 by tissue type. Methods: Dynamic PET-CT over the lower abdomen and static whole-body PET-CT 80–90 min p.i. from 142 patients with biochemical recurrence were retrospectively analysed. Detection rates were compared to PSA levels. Average time-activity curves were calculated from tumour lesions and normal tissue. A three-compartment model and non-compartment model were used to calculate tumour kinetics. Results: Overall detection rate was 70.42%, and in patients with PSA > 0.4 ng/mL 76.67%. All tumour lesions presented the steepest standardised uptake value (SUV) incline in the first 7–8 min before decreasing to different degrees. Normal tissue presented with a low uptake, except for the bladder, which accumulated activity the steepest 15–16 min. p.i.. While all tumour lesions continuously increased, bone metastases showed the steepest decline, resulting in a significantly lower SUV than lymph node metastases (60 and 80–90 min). Transport rate from the blood and tracer binding and internalisation rate were lower in bone metastases. Heterogeneity (fractal dimension) and vascular density were significantly lower in bone metastases. Conclusion: Even at low PSA between 0.51 and 0.99 ng/mL, detection rate was 57%. Dynamic imaging showed a time window in the first 10 min where tumour uptake is high, but no bladder activity is measured, aiding accuracy in distinction of local recurrence. Kinetic modelling provided additional information for tumour characterisation by tissue type.

Dear Editor, Recently, Kitahara et al. (2019) published an article in JAMA Internal Medicine entitled "Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism". This publication was based on organ dosimetry calculations from 18,805 patients with hyperthyroidism treated with radioiodine treatment (RAI) followed for nearly 7 decades. The results of the work suggest that solid cancer mortality increases in hyperthyroid patients treated with RAI, with greater absorbed doses to exposed organs being associated with increased risk of death. As expected, these -undoubtedly interesting- findings have raised serious concerns in both physicians and patients regarding the safety profile of RAI. Driven by this, we aim to critically read the article and highlight some of the limitations of the study. First of all, the authors provide data on the association of RAI with cancer mortality and not with cancer incidence, which may be an interesting approach, but constitutes at the same time a weakness of the study. The authors' choice to investigate RAI as a progression and not as an actual risk factor for the onset of malignancies in hyperthyroid patients may be interpreted as an inability to document a causal relationship between them. It would be methodologically more correct either to examine as confounders -among others- cancer stage, patients' age and other co-morbidities, previous treatment administered, or to declare the absence of these data as a major limitation of the conducted analysis. Moreover, the negligence of the role of thyroid hormone levels is another fundamental limitation of this analysis, since a large body of the literature has documented the association of increased thyroid hormone levels with carcinogenicity. In their introduction, the authors state that RAI has declined in favor of antithyroid drugs (ATD). This trend is attempted to be explained by the "increased awareness" of an association between RAI and Graves ophthalmopathy exacerbation as well as radiation-induced secondary malignancies. This argument has however little supporting evidence, since several studies demonstrate that ATD remain the least commonly used agents through the last decades. Moreover, the authors neglect that ATD carry a statistically significant and more obvious cancer death risk than RAI. On the other hand, the use of RAI as index therapy has been doubled through the decades, influenced by several causes including patient-, disease-, physician- and health system- related factors and, of course, not only patients' and physicians' "increased awareness". In addition, concerns are raised regarding organ dosimetry calculations with large uncertainties introduced in the analysis due to reported errors in measured thyroid uptake and mass as well as same model parameters used for patients with different thyroid entities. As Tulchinsky and Bertrand Brill -the Nuclear Medicine physician coauthors of the JAMA paper- state, 'the Kitahara et al. (2019) publication provides a numerical estimate of excess cancer deaths after RAI using assumptive model-based calculations' but 'no excess cancer deaths were actually observed after RAI relative to that predicted in contemporaneous population (using standardized mortality ratio analyses)'. Further, the authors report that "Malignancy was the primary cause for 2,366 deaths (15.3%)" without mentioning other causes of death. However, it would be appropriate to provide some data at least on cardiovascular disease (CVD)-related mortality given that thyrotoxicosis has been associated with CVD by a large number of studies. Some other methodological limitations include the lack of more appropriate control groups for comparison, such as hyperthyroid patients treated with other treatments (surgery, ATD or both), hyperthyroid patients without treatment, as well as euthyroid patients. Finally, the lack of multivariate analyses for all the aforementioned confounders as well as the lack of detailed description of "Other risk factors (x)" in the applied model: "background (a, s, b, x)[1+βd*f(y)]" constitute methodological drawbacks of the analysis. The key-point of the analysis-thankfully mentioned by the authors- is summarized by the phrase: "some results may be because of chance; therefore, the results should be interpreted with caution." And we could not agree more.

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy usually arising as a nonspecific nodule on sun-exposed areas of the head and neck. Given the poor prognosis of this aggressive tumor, assessment of disease burden in pre-and post-treatment care may ensure an optimal management with significant implications for patient surveillance and prognosis. Although imaging has established its role in locally advanced or distant metastatic MCC, a standard imaging algorithm is yet to be determined and respective recommendations are mainly based on melanoma. Positron emission tomography/computed tomography (PET/CT) is increasingly evolving as a valuable imaging tool in metastatic or unresectable MCC, mostly utilizing the glucose analogue18 F-fluorodeoxyglucose (18F-FDG) as a radiotracer. Despite being inferior in detecting the disease in its early stages compared to the “gold standard” of sentinel lymph node biopsy, recent evidence suggests an important role for18F-FDG PET/CT in the routine workup of localized MCC. Moreover, 68 Ga-labeled somatostatin analogues have been employed as PET tracers in the field of MCC with promising, yet comparable to18F-FDG, results. This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

BACKGROUND Since their clinical introduction in 2011, PSMA-PET/CT (PSMA: prostate-specific membrane antigen) as well as PSMA therapy of prostate cancer (PC) have spread rapidly worldwide. OBJECTIVES To summarize the current knowledge about both PSMA-PET/CT and PSMA therapy of PC. METHODS The knowledge derived from the literature as well as the authors' experiences were collected in this review. RESULTS PSMA-PET/CT demonstrates a very high sensitivity and specificity for the detection of recurrent PC as well as for the primary staging of intermediate- and high-risk PC. PSMA therapy shows promising results in third-line treatment for patients with castration-resistant, metastatic PC. CONCLUSIONS PSMA-PET/CT is meanwhile established as the gold standard for the detection of recurrent PC and is in the process of assuming the same role for primary staging of intermediate- to high-risk PC. PSMA therapy serves as a promising third-line therapy in an increasing number of centers.

Background: PET/CT with F-18-fluorodeoxyglucose (FDG) images of patients suffering from metastatic melanoma have been analysed using fractal and multifractal analysis to assess the impact of monoclonal antibody ipilimumab treatment with respect to therapy outcome. Results: Thirty-one cases of patients suffering from metastatic melanoma have been scanned before and after two and after four cycles of treatment. For each patient, we calculated the fractal and multifractal dimensions using the box-counting method on the digitalised PET/CT images of all three studies to assess the therapeutic outcome. We modelled the spreading of malignant cells in the body via kinetic Monte Carlo simulations to address the dynamical evolution of the metastatic process and to predict the spatial distribution of malignant lesions. Our analysis shows that the fractal dimensions which describe the tracer dispersion in the body decrease consistently with the deterioration of the patient’s therapeutic outcome condition. In 20 out of 24 cases, the fractal analysis results match those of the treatment outcome as defined by the oncologists, while 7 cases are considered as special cases because the patients had non-tumour-related findings or side effects which affect the results. The decrease in the fractal dimensions with the deterioration of the patient conditions (in terms of disease progression) is attributed to the hierarchical localisation of the tracer which accumulates in the affected lesions and does not spread homogeneously throughout the body. Fractality emerges as a result of the migration patterns which the malignant cells follow for propagating within the body (circulatory system, lymphatic system). Analysis of the multifractal spectrum complements and supports the results of the fractal analysis. In the kinetic Monte Carlo modelling of the metastatic process, a small number of malignant cells diffuse through a fractal medium representing the blood circulatory network. Along their way, the malignant cells engender random metastases (colonies) with a small probability and, as a result, fractal spatial distributions of the metastases are formed similar to the ones observed in the PET/CT images. Conclusions: The Monte Carlo-generated spatial distribution of metastases changes with time approaching values close to the ones recorded in the metastatic patients. Thus, we propose that fractal and multifractal analyses have potential applications in quantification of the evaluation of PET/CT images to monitor the disease evolution as well as the response to different medical treatments. The proposed approach, being operator independent, can offer new diagnostic tools in parallel to the visual location of the lesions and may improve multiparameter assessment of FDG PET/CT studies. © 2016, The Author(s).

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