Extraosseous distribution of 99mTc-diphosphonates during bone scintigraphy: review of the literature with case series presentation.

PURPOSE: Technetium-99m (99mTc)-diphosphonates represent the most common radiopharmaceutical used for bone scintigraphy. Even if the uptake in bone tissue has been widely explored, atypical uptake could be seen in soft tissue malignancies during bone scintigraphy. Increased vascularization and endothelium permeability represent front-row players in the biodistribution of the tracer, albeit other causes have been identified such as trauma, necrosis, the presence of calcification in metastasis, the pH of the tissue and consequently the type of ion concentration. CONCLUSION: The aim of this paper is to summarize the state of art of atypical soft tissue uptake seen in cancer tissues. The research was conducted on PubMed. The analysis of the literature suggests that calcium metabolism and ionic saturation have a pivotal role in the biodistribution of bone tracers. This phenomenon ranks in a complex scenario that includes carcinogenesis and cancer environment aspects. We also report two cases in our Institution in which atypical uptake in cancer tissues was observed.

The Prognostic Role of [18F]FDG PET/CT in Patients with Advanced Cutaneous Squamous Cell Carcinoma Submitted to Cemiplimab Immunotherapy: A Single-Center Retrospective Study.

Background: Baseline 2-deoxy-2[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET)-derived parameters and 12-week metabolic response were investigated as prognostic factors in advanced cutaneous squamous cell carcinoma (cSCC) submitted to cemiplimab immunotherapy. Materials and Methods: Clinical records of 25 cSCC patients receiving cemiplimab, submitted to [18F]FDG positron emission tomography/computed tomography (PET/CT) at baseline and after ∼12 weeks, were retrospectively reviewed. The Kaplan-Meier (KM) method was applied to analyze differences in event-free survival (EFS), and Cox regression analysis was employed to identify the prognostic factors. Results: At the 12-week PET/CT evaluation, 16 patients (64%) were classified as responders (complete or partial response) and 9 (36%) as nonresponders ("unconfirmed progressive metabolic disease") according to immune PET Response Criteria in Solid Tumors (iPERCIST). By KM analysis, baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) significantly correlated with the EFS (p < 0.05). Furthermore, the KM analysis showed that the lack of metabolic response at 12 weeks was associated with meaningfully shorter EFS (7.2 ± 1 months in nonresponders vs. 20.3 ± 2.3 months in responders). In Cox multivariate analysis, metabolic response at 12 weeks remained the only predictor of the EFS (p < 0.05). Conclusions: Baseline tumor load (i.e., MTV and TLG) and metabolic response at 12 weeks may have a prognostic impact in cSCC patients treated with cemiplimab.

Functional Imaging in Musculoskeletal Disorders in Menopause.

Menopause-related musculoskeletal (MSK) disorders include osteoporosis, osteoarthritis (OA), sarcopenia and sarco-obesity. This review focuses on the applications of nuclear medicine for the functional imaging of the aforementioned clinical conditions. Bone Scan (BS) with 99mTc-labeled phosphonates, alone or in combination with MRI, can identify "fresh" vertebral collapse due to age-associated osteoporosis and provides quantitative parameters characterized by a good correlation with radiological indices in patients with OA. 18F-NaF PET, particularly when performed by dynamic scan, has given encouraging results for measuring bone turnover in osteoporosis and allows the evaluation of subchondral bone metabolic activity in OA. FDG PET can help discriminate between pathological and nonpathological vertebral fractures, especially by applying appropriate SUV-based thresholds. In OA, it can effectively image inflamed joints and support appropriate clinical management. Preliminary evidences suggest a possible application of FDG in sarco-obesity for the detection and quantification of visceral adipose tissue (VAT). Further studies are needed to better define the role of nuclear medicine in menopause-related MSK disease, especially as regards the possible impact of new radiopharmaceuticals (ie, FAPI and RGD peptides) and recent technological advances (eg, total-body PET/CT scanners).

NECTIN-4 targeted theranostics for urothelial cancer: getting ready for primetime?

Locally advanced and metastatic urothelial carcinoma (UC) presents a bleak prognosis, with limited treatment options. NECTIN-4, an overexpressed protein in UC, has become a target for therapy. Enfortumab vedotin (EV) gained Food and Drug Administration approval for advanced UC treatment, but patient selection based on NECTIN-4 expression remains challenging. In the study under evaluation, Duan et al. introduced a novel PET/CT imaging approach using 68Ga-N188, a molecular probe, to visualize NECTIN-4 expression in UC. Their study encompassed preclinical evaluations and translational assessments in both healthy individuals and UC patients. Results demonstrated the potential of 68Ga-N188 in identifying NECTIN-4 expression in UC lesions. Additionally, the study utilized long axial field-of-view (LAFOV) PET/CT, enhancing sensitivity and enabling dynamic studies for improved radiopharmaceutical evaluation. In summary, the study from Duan and colleagues introduces a promising molecular imaging technique that could aid in patient selection for EV therapy and the development of targeted drugs for UC. It also highlights the potential of LAFOV PET/CT in enhancing imaging precision and expanding future therapeutic possibilities for UC.

Optimising Radioligand Therapy for Patients with Gastro-Entero-Pancreatic Neuroendocrine Tumours: Expert Opinion from an Italian Multidisciplinary Group.

Radioligand therapy (RLT) with lutetium (177Lu) oxodotreotide is an approved therapy in combination with somatostatin analogues (SSAs) for patients with advanced, well-differentiated G1-G2, gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs) that progress on SSAs. We conducted a series of round table meetings throughout Italy to identify issues related to RLT delivery to patients with GEP-NETs. Four key issues were identified: (1) the proper definition of tumour progression prior to RLT initiation; (2) the impact of RLT in patients with bone metastases and/or high hepatic tumour burden; (3) the optimal follow-up protocol after RLT; and (4) organisational issues related to RLT use and managerial implications. This article reviews the literature relating to the aforementioned issues and makes recommendations based on available evidence and Italian NET experts' opinions. In particular, the group recommends the development of a diagnostic-therapeutic care pathway (DTCP) for patients undergoing RLT which provides systematic guidance but can still be individualised for each patient's clinical and psychosocial needs. A DTCP may clarify the diagnostic, therapeutic and post-treatment monitoring process, and improve communication and the coordination of care between hub and spoke centres. The DTCP may also contribute to changes in the care process related to the 2013/59/EURATOM Directive and to the definition of costs when planning for future or updated reimbursement of RLT in Italy.

Molecular imaging of PARP in cancer: state-of-the-art.

INTRODUCTION: Poly-ADP-ribose-polymerase inhibitors (PARPi), which exploit the processes of so-called 'synthetic lethality,' have been successfully implemented in oncological practice. However, not all patients respond to PARPi, and there is an unmet need for noninvasive biomarkers suitable for patient selection and monitoring during PARPi therapy. AREAS COVERED: The first clinical applications of molecular imaging with positron emission tomography/computed tomography (PET/CT) with [18F]-FluorThanatrace ([18F]-FTT) and [18F]-PARPi, highly effective PARP-ligands, in patients with several malignancies (head and neck, ovarian, prostate, and breast cancer) are covered, with a particular focus on its potential for pre-treatment selection and follow-up. EXPERT OPINION: By a search made on the most common database, such as PubMed and Google Scholar in a period from January 2010 and 2023, first clinical evidence suggests that PET/CT with [18F]-FTT and [18F]-PARPi might represent a reliable tool for in vivo imaging and quantification of PARP-1 expression in ovarian, prostate, breast, head, and neck cancer, supporting their potential usefulness for patient selection before PARPi-therapies. In addition, a reduction in [18F]-FTT uptake has been registered after therapy initiation and seems to be correlated with patient outcome after PARPi-based regimens. Further studies are needed to better address the value of PARPI-radiolabeled PET imaging in these clinical settings, especially as it concerns technical features such as optimal scan modality (dynamic vs. static) and timing.

Sleep Dysregulation Is Associated with 18F-FDG PET and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease.

Background: Sleep impairment has been commonly reported in Alzheimer's disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. Objective: The present study investigated cerebrospinal-fluid (CSF) and 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). Methods: MCI and AD patients underwent PSG, 18F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Results: Thirty-five patients were included in the study (9 MCI and 26 AD patients). 18F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p = 0.013) and positively with REM sleep (p = 0.033). 18F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p = 0.042), Non-REM stage 1 of sleep (p = 0.031), wake after sleep onset (p = 0.028), and lower sleep efficiency (p = 0.045). CSF levels of Aß42 correlated negatively with the wake bouts index (p = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p = 0.045) and time in bed (p = 0.031), respectively. Conclusion: Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers.

Myocardial Functional Imaging in Pediatric Nuclear Cardiology.

The role of nuclear medicine in pediatric cardiology has grown rapidly over the years, providing useful functional and prognostic information and playing a complementary role to morphological imaging in the evaluation of myocardial perfusion, cardiovascular inflammation and infections, and cardiac sympathetic innervation. The aim of this narrative review is to summarize and highlight the most important evidence on pediatric nuclear cardiology, describing clinical applications and the possibilities, advantages, and limitations of nuclear medicine techniques. Moreover, a special focus will be given to the minimization of radiation exposure in pediatric nuclear cardiology imaging, a critical topic in children.

The new bone WB-SPECT/CT: hybrid, from head-to-toe and digital! Is it worth the effort?

INTRODUCTION: A bone scan (BS) plays a pivotal role in many oncological and non-oncological conditions. The planar BS is characterized by high sensitivity but low specificity. With respect to planar imaging, the implementation of single-photon emission computed tomography (SPECT) has allowed increased image contrast and more accurate tracer localization. AREAS COVERED: Recent technological innovations in the field of BS are treated, with a particular focus on multi-field-of-view devices allowing to cover the entire scan length with a 3D acquisition (WB-SPECT/CT). In addition, the applications of cadmium zinc telluride/CzT detectors capable of converting gamma photons directly into electrical impulses (i.e. 'digital SPECT') are discussed. EXPERT OPINION: Initial clinical experiences indicate that WB-SPECT/CT is characterized by higher sensitivity, diagnostic accuracy, and increased confidence in image interpretation with respect to the 'old-fashioned' BS (planar images with or without a single field-of-view SPECT). Furthermore, CzT-based detectors, thanks to their superior sensitivity, might be helpful to implement fast acquisition protocols. Further studies are needed to better define the clinical impact of bone CzT WB-SPECT/CT on patients' management and outcome, as well as its cost-benefit ratio.

[18F]-FDHT PET for the Imaging of Androgen Receptor in Prostate and Breast Cancer: A Systematic Review.

The aim of this systematic review is to provide a comprehensive overview of the role of fluoro-5α-dihydrotestosterone ([18F]-FDHT) for the in vivo imaging of androgen receptors (AR) through positron emission tomography (PET) in metastatic breast (mBC) and metastatic castration-resistant prostate cancer (mCRPC). Relevant studies published from 2013 up to May 2023 were selected by searching Scopus, PubMed and Web of Science. The selected imaging studies were analyzed using a modified version of the critical Appraisal Skills Programme (CASP). Eleven studies encompassing 321 patients were selected. Seven of the eleven selected papers included 266 subjects (82.2%) affected by mCRPC, while four encompassed 55 (17.2%) patients affected by mBC. [18F]-FDHT PET showed a satisfying test/retest reproducibility, and when compared to a histochemical analysis, it provided encouraging results for in vivo AR quantification both in mCRPC and mBC. [18F]-FDHT PET had a prognostic relevance in mCRPC patients submitted to AR-targeted therapy, while a clear association between [18F]-FDHT uptake and the bicalutamide response was not observed in women affected by AR-positive mBC. Further studies are needed to better define the role of [18F]-FDHT PET, alone or in combination with other tracers (i.e., [18F]-FDG/[18F]-FES), for patients' selection and monitoring during AR-targeted therapy, especially in the case of mBC.

Novel Theranostic Approaches Targeting CCR4-Receptor, Current Status and Translational Prospectives: A Systematic Review.

BACKGROUND: With the high mortality rate of malignant tumors, there is a need to find novel theranostic approaches to provide an early diagnosis and targeted therapy. The chemokine receptor 4 (CCR4) is highly expressed in various tumors and plays an important role in tumor pathogenesis. This systematic review aims to provide a complete overview on clinical and preclinical applications of the CCR4 receptor as a target for theranostics, using a systematic approach to classify and assemble published studies performed on humans and animals, sorted by field of application and specific tumor. METHODS: A systematic literature search of articles suiting the inclusion criteria was conducted on Pubmed, Scopus, Central, and Web of Science databases, including papers published from January 2006 to November 2022. Eligible studies had to be performed on humans and/or in vivo/in vitro studying CCR4 expression in tumors. The methodological quality was assessed through the Critical Appraisal Skills Programme (CASP) assessing only the studies performed on humans. RESULTS: A total of 17 articles were screened. The articles were assessed for eligibility with the exclusion of 4 articles. Ultimately, 13 articles were selected for the qualitative analysis, and six articles were selected for the critical appraisal skills program. CONCLUSIONS: The development of new radionuclides and radiopharmaceuticals targeting CCR4 show promising results in the theranostics of CCR4 sensible tumors. Although to widen its use in clinical practice, further translation of preclinical to clinical data is needed.

Hepato-Biliary Imaging in an Acute Setting: Is There a Role for Nuclear Medicine?

Nuclear medicine (NM) is not commonly considered as a first-line imaging modality in hepato-biliary (HB) emergencies. The aim of this review is to provide an update on the potential of NM for the imaging of HB emergencies. 99mTc-HIDA scintigraphy showed high diagnostic accuracy for acute cholecystitis, thus being particularly useful in patients at high-risk for surgery due to comorbidities and with no clear findings at US or CT. Although limitedly explored, White blood cell (WBC) scan might have a role in case of acute pancreatitis, especially for the imaging of pancreatic leukocyte infiltration and the prediction of pancreatic necrosis. Scientific literature on 18F-FDG-PET/CT in HB acute disease mainly consists of case reports or case series, describing incidental findings in oncological PET/CT scans. In patients with obstructive jaundice, PET/CT has been proposed to disclose and characterize occult tumoral etiology. Further studies are needed to evaluate the clinical usefulness of the various NM approaches in HB acute settings, particularly with respect to the emerging new technologies (eg, PET/MRI) and radiopharmaceuticals.

Head-to-Head Comparison between FDG and 11C-Methionine in Multiple Myeloma: A Systematic Review.

The aim of this systematic review is to provide a comprehensive overview of the existing literature, comparing 18F-fluorodeoxyglucose (FDG) and 11C-methionine (MET) for the imaging of multiple myeloma (MM) with positron emission computed tomography (PET/CT). Relevant studies published from 2013 up to March 2023 were selected by searching Scopus, PubMed, and Web of Science. Selected imaging studies were analyzed using a modified version of the critical Appraisal Skills Programme (CASP). Ten studies encompassing 335 patients were selected. On a patient-based analysis, MET sensitivity ranged between 75.6% and 100%, resulting higher than that measured for FDG (0-100%). MET outperformed FDG for the detection of focal lesions, diffuse bone marrow involvement and mixed patterns. PET-derived parameters resulted higher for MET than for FDG, with a strong correlation with clinical variables (e.g., monoclonal component and beta-2-microglobulin levels, bone marrow infiltration, etc.), although FDG maintained a prognostic impact on outcome prediction. When compared to other tracers or imaging modalities, MET showed stronger correlation and inter-observer agreement than FDG. Although biased by the small cohorts and requiring confirmation through multicenter studies, preliminary findings suggest that MET-PET should be preferred to FDG for PET imaging of MM, or alternatively used as a complementary imaging modality. Some issues, such as tracer availability and the role of MET with respect to other emerging tracers (i.e., 68Ga-pentixafor, 18F-FACBC and 18F-FET), should be the topic of further investigations.

What radiolabeled FAPI pet can add in breast cancer? A systematic review from literature.

To provide an overview of the current available data about FAPI PET in breast cancer patients, with a perspective point of view. A literature search for studies about FAPI PET in the last 5 years (from 2017 to January 2023) was carried out on MEDLINE databases, such as PubMed, EMBASE, Web of Science and Google Scholar using the following keywords: "PET" AND "FAPI" AND "Breast Cancer" AND "Fibroblast imaging". The Critical Appraisal Skills Program (CASP) checklist for diagnostic test studies was used for testing the quality of selected papers. 13 articles were selected, including 172 patients affected by breast cancer who underwent FAPI-based PET images. CASP checklist was used in 5/13 papers, demonstrating a general low quality. Different types of FAPI-based tracers were used. No difference in terms of FAPI uptake was reported based on the histopathological characteristics, such as immunohistochemistry and grading of breast cancer. FAPI demonstrated more lesions and yielded much higher tumor-to-background ratios than 2-[18F]FDG. Preliminary experiences with FAPI PET in breast cancer showed some advantages than the current available 2-[18F]FDG, although prospective trials are needed to further evaluate its diagnostic utility in clinical practice.

Radiolabeled FAPI in pancreatic cancer: can it be an additional value in the management of patients?

INTRODUCTION: To discuss the current evidence about radiolabeled-FAPI in patients affected by pancreatic cancer by underlying the advantages, disadvantages, and the future perspectives also in the theragnostic field. AREAS COVERED: A literature search up until February 2023 was performed in PubMed, EBSCO, and EMBASE databases. Clinical reports, conference abstracts, editorials, and letters-to-the-editor were excluded. The results were presented according to the PRISMA guidelines. The quality of studies was evaluated by using the Critical Appraisal Skill Program checklist. EXPERT OPINION: From the initial 139 studies, 21 papers were selected for the final analysis. Ten papers were related to FAPI-uptake in health/benign/malignant pancreas, eight studies were focalized on the utility of radiolabeled-FAPI for the identification of premalignant and malignant pancreatic lesions and only three papers were related to the the theragnostic approach. Only two papers enrolled exclusively patients with pancreatic cancer undergoing FAPI-PET. In total, 55 patients underwent FAPI-PET for the identification of the suspicious mass/primary tumor (n = 43) and recurrent disease (n = 12). In both the studies, FAPI-PET detected more lesions than 2-[18F]FDG. Preliminary data about the FAPI-based theragnostic approach in patients with pancreatic cancer (n = 9 patients, totally) are now available. Radiolabeled-FAPI is a promising agent for the identification of pancreatic malignant lesions, but further prospective studies are still necessary.

Clinical Applications of TSPO PET for Glioma Imaging: Current Evidence and Future Perspective-A Systematic Review.

Our aim was to provide a comprehensive overview of the existing literature concerning the clinical applications of positron emission computed tomography (PET) with radiopharmaceuticals targeting the translocator protein (TSPO) in gliomas. A literature search for studies about TSPO PET in the last 10 years (from 2013 to February 2023) was carried out on PubMed, Scopus, and Web of Science using the following keywords: "PET" AND "Gliomas" AND "TSPO". The Critical Appraisal Skills Program checklist for diagnostic test studies was used for testing the quality of selected papers. Ten articles were selected, encompassing 314 glioma patients submitted to PET/CT (9/10) or PET/MRI (1/10) with TSPO ligands. Among the various available TSPO tracers, the most frequently used was the third-generation ligand, [18F]-GE-180. TSPO PET results were useful to identify anaplastic transformation in gliomas and for the prognostic stratification of patients bearing homogeneous genetic alterations. When compared to amino-acid PET, TSPO PET with [18F]-GE-180 presented superior image quality and provided larger and only partially overlapping PET-based volumes. Although biased by some issues (i.e., small sample size, most of the studies coming from the same country), preliminary applications of TSPO PET were encouraging. Further studies are needed to define implications in clinical practice and shape the role of TSPO PET for patients' selection for potential TSPO-targeted molecular therapies.

Integrated use of 90Y-labeled microspheres and immune checkpoint inhibitors in hepatic tumors: current status and future directions.

INTRODUCTION: Transarterial radioembolization (TARE) with yttrium-90 (90Y)-labeled microspheres and immune check-point inhibitors (ICIs) have been successfully applied for the management of advanced hepatocellular carcinoma (HCC) and hepatic metastases. The potential synergism of 90Y-microspheres and ICIs in integrated therapeutic regimens represents a topic of great interest. AREAS COVERED: The main characteristics of resin and glass 90Y-microspheres are covered, as well as the basic principles of TARE. Furthermore, the existing literature on the integrated use of 90Y-microspheres with ICIs in HCC and hepatic metastases are discussed. EXPERT OPINION: 90Y-microspheres and ICIs have been employed in integrated approaches in patients with advanced HCC, liver metastases from uveal melanoma (UMLM) and colorectal cancer (CRCLM). In all cases, toxicity profile results were tolerable. A favorable impact on survival was registered for HCC and UMLM, but 90Y-microspheres did not help sensitize microsatellite-stable CRCLM to immunotherapy. Particular caution should be paid in UMLM patients undergoing combination therapy with ipilimumab plus nivolumab. In this regard, the potential usefulness of provisional dosimetry to estimate the radiation burden delivered to the normal hepatic parenchyma has still to be fully addressed.

Association between hearing sensitivity and dopamine transporter availability in Parkinson's disease.

In a previous study, we observed: (i) significant hearing function impairment, assessed with pure tone audiometry and distortion product otoacoustic emissions, in patients with Parkinson's disease, compared with a matched control group, and (ii) lateralization of the hearing dysfunction, worse on the side affected by more pronounced Parkinson's disease motor symptoms. This study investigates the association between the basal ganglia dopamine transporter availability and the hearing function in Parkinson's disease patients, focusing also on the lateralization of both dysfunctions, with respect to that of the motor symptoms, and introducing a further distinction between patients with left-sided and right-sided predominant motor symptoms. Patients with right-handed Parkinson's disease with a recent estimation of 123I-FP-CIT striatal uptake were audiologically tested with pure tone audiometry and distortion product otoacoustic emissions. Thirty-nine patients were included in the study. A statistically significant association was found, in the left-side predominant group only, between the distortion product otoacoustic emission levels and the contralateral dopamine transporter availability, and between the hearing threshold and the dopamine transporter availability difference between the ipsi- and the contralateral sides. The hearing impairment lateralization correlated to the motor symptom asymmetry was found significant only in the left-side predominant patients. The association between hearing function and basal ganglia dopamine transporter availability supports the hypothesis that the peripheral hearing function decline associated with dopamine depletion is involved in Parkinson's disease development, with a significant difference between patients with left- and right-sided predominant motor symptoms. These findings also suggest that peripheral hearing function evaluation and its lateralization could be key elements for subtyping the disease.