Prostate-Specific Membrane Antigen Radioligand Therapy in Non-Prostate Cancers: Where Do We Stand?

INTRODUCTION: The term theragnostic refers to the combination of a predictive imaging biomarker with a therapeutic agent. The promising application of prostate-specific membrane antigen (PSMA)-based radiopharmaceuticals in the imaging and treatment of prostate cancer (PCa) patients opens the way to investigate a possible role of PSMA-based radiopharmaceuticals in cancers beyond the prostate. Therefore, the aim of this review was to evaluate the role of 177Lu-PSMA radioligand therapy (RLT) in malignancies other than prostate cancer by evaluating preclinical, clinical studies, and ongoing clinical trials. METHODS: An extensive literature search was performed in three different databases using different combinations of the following terms: "Lu-PSMA", "177Lu-PSMA", "preclinical", "mouse", "salivary gland cancer", "breast cancer", "glioblastoma", "solid tumour", "renal cell carcinoma", "HCC", "thyroid", "salivary", "radioligand therapy", and "lutetium-177". The search had no beginning date limit and was updated to April 2024. Only articles written in English were included in this review. RESULTS: A total of four preclinical studies were selected (breast cancer model n = 3/4). PSMA-RLT significantly reduced cell viability and had anti-angiogenic effects, especially under hypoxic conditions, which increase PSMA binding and uptake. Considering the clinical studies (n = 8), the complexity of evaluating PSMA-RLT in cancers other than prostate cancer was clearly revealed, since in most of the presented cases a sufficient tumour radiation dose was not achieved. However, encouraging results can be found in some types of diseases, such as thyroid cancer. Some clinical trials are still ongoing, and results from prospective larger cohorts of patients are awaited. CONCLUSIONS: The need for larger patient cohorts and more RLT cycles administered underscores the need for further comprehensive studies. Given the very preliminary results of both preclinical and clinical studies, ongoing clinical trials in the near future may provide stronger evidence of both the safety and therapeutic efficacy of PSMA-RLT in malignancies other than prostate cancer.

FAPi-Based Agents in Thyroid Cancer: A New Step towards Diagnosis and Therapy? A Systematic Review of the Literature.

(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to 131I, becoming more aggressive. In this scenario, [18F]FDG PET/CT imaging is used for evaluating the widespread nature of the disease, despite its low sensitivity and a false negative rate of 8-21.1%. A novel class of PET agents targeting the fibroblast activation protein inhibitor (FAPi) has emerged, studied particularly for their potential application to theranostics. (2) Methods: A search of the literature was performed by two independent authors (P.G. and L.E.) using the PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE databases. The following terms were used: "FAP" or "FAPi" or "Fibroblast activating protein" and "thyroid" or "thyroid cancer", in different combinations. The included papers were original articles, clinical studies, and case reports in the English language. No time limits were used. Editorials, conference papers, reviews, and preclinical studies were excluded. (3) Results: There were 31 papers that were selected. Some studies reported a low or absent FAPi uptake in TC lesions; others reported promising findings for the detection of metastases. (4) Conclusions: The preliminary results are encouraging. FAPI agents are an alternative to [18F]FDG and a promising theranostic tool. However, further studies with a larger population are needed.

Emerging Role of [18F]FLT PET/CT in Lymphoid Malignancies: A Review of Clinical Results.

Fluorine-18 fluorodeoxyglucose ([18F]FDG) is nowadays the leading positron emission tomography (PET) tracer for routine clinical work-ups in hematological malignancies; however, it is limited by false positive findings. Notably, false positives can occur in inflammatory and infective cases or in necrotic tumors that are infiltrated by macrophages and other inflammatory cells. In this context, 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been shown to be a promising imaging biomarker of hematological malignant cell proliferation. In this review, a total of 15 papers were reviewed to collect literature data regarding the clinical application of [18F]FLT PET/CT in hematological malignancies. This imaging modality seems to be a suitable tool for noninvasive assessment of tumor grading, also showing a correlation with Ki-67 immunostaining. Moreover, [18F]FLT PET/CT demonstrated high sensitivity in detecting aggressive lymphoma lesions, especially when applying a standardized uptake value (SUV) cutoff of 3. At baseline, the potential of [18F]FLT imaging as a predictive tool is demonstrated by the low tracer uptake in patients with a complete response. However, its use is limited in evaluating bone diseases due to its high physiological uptake in bone marrow. Interim [18F]FLT PET/CT (iFLT) has the potential to identify high-risk patients with greater precision than [18F]FDG PET/CT, optimizing risk-adapted therapy strategies. Moreover, [18F]FLT uptake showed a greater ability to differentiate tumor from inflammation compared to [18F]FDG, allowing the reduction of false-positive findings and making the first one a more selective tracer. Finally, FLT emerges as a superior independent predictor of PFS and OS compared to FDG and ensures a reliable early response assessment with greater accuracy and predictive value.

Head-to-Head Comparison of FDG and Radiolabeled FAPI PET: A Systematic Review of the Literature.

FAPI-based radiopharmaceuticals are a novel class of tracers, mainly used for PET imaging, which have demonstrated several advantages over [18F]FDG, especially in the case of low-grade or well-differentiated tumors. We conducted this systematic review to evaluate all the studies where a head-to-head comparison had been performed to explore the potential utility of FAPI tracers in clinical practice. FAPI-based radiopharmaceuticals have shown promising results globally, in particular in detecting peritoneal carcinomatosis, but studies with wider populations are needed to better understand all the advantages of these new radiopharmaceuticals.

Medication and ECG Patterns That May Hinder SPECT Myocardial Perfusion Scans.

Coronary artery disease (CAD) is the leading cause of death followed by cancer, in men and women. With risk factors being endemic and the increasing costs of healthcare for management and treatment, myocardial perfusion imaging (MPI) finds a central role in risk stratification and prognosis for CAD patients, but it comes with its limitations in that the referring clinician and managing team must be aware of and use at their advantage. This narrative review examines the utility of myocardial perfusion scans in the diagnosis and management of patients with ECG alterations such as atrioventricular block (AVB), and medications including calcium channel blockers (CCB), beta blockers (BB), and nitroglycerin which may impact the interpretation of the exam. The review analyzes the current evidence and provides insights into the limitations, delving into the reasons behind some of the contraindications to MPI.

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.

Imaging of Tauopathies with PET Ligands: State of the Art and Future Outlook.

(1) Background: Tauopathies are a group of diseases characterized by the deposition of abnormal tau protein. They are distinguished into 3R, 4R, and 3R/4R tauopathies and also include Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Positron emission tomography (PET) imaging represents a pivotal instrument to guide clinicians. This systematic review aims to summarize the current and novel PET tracers. (2) Methods: Literature research was conducted on Pubmed, Scopus, Medline, Central, and the Web of Science using the query "pet ligands" and "tauopathies". Articles published from January 2018 to 9 February, 2023, were searched. Only studies on the development of novel PET radiotracers for imaging in tauopathies or comparative studies between existing PET tracers were included. (3) Results: A total of 126 articles were found, as follows: 96 were identified from PubMed, 27 from Scopus, one on Central, two on Medline, and zero on the Web of Science. Twenty-four duplicated works were excluded, and 63 articles did not satisfy the inclusion criteria. The remaining 40 articles were included for quality assessment. (4) Conclusions: PET imaging represents a valid instrument capable of helping clinicians in diagnosis, but it is not always perfect in differential diagnosis, even if further investigations on humans for novel promising ligands are needed.

A Systematic Review on Dementia and Translocator Protein (TSPO): When Nuclear Medicine Highlights an Underlying Expression.

BACKGROUND: Translocator protein (TSPO) is a neuroinflammation hallmark. Different TSPO affinity compounds have been produced and over time, the techniques of radiolabeling have been refined. The aim of this systematic review is to summarize the development of new radiotracers for dementia and neuroinflammation imaging. METHODS: An online search of the literature was conducted in the PubMed, Scopus, Medline, Cochrane Library, and Web of Science databases, selecting published studies from January 2004 to December 2022. The accepted studies considered the synthesis of TSPO tracers for nuclear medicine imaging in dementia and neuroinflammation. RESULTS: A total of 50 articles was identified. Twelve papers were selected from the included studies' bibliographies and 34 were excluded. Thus, 28 articles were ultimately selected for quality assessment. CONCLUSION: Huge efforts in developing specific and stable tracers for PET/SPECT imaging have been made. The long half-life of 18F makes this isotope a preferable choice to 11C. An emerging limitation to this however is that neuroinflammation involves all of the brain which inhibits the possibility of detecting a slight inflammation status change in patients. A partial solution to this is using the cerebellum as a reference region and developing higher TSPO affinity tracers. Moreover, it is necessary to consider the presence of distomers and racemic compounds interfering with pharmacological tracers' effects and increasing the noise ratio in images.

Role of Exendin-4 Functional Imaging in Diagnosis of Insulinoma: A Systematic Review.

BACKGROUND: Insulinomas are the most common neuroendocrine neoplasms of the pancreas. Diagnosis is made through patient clinical presentation with hypoglycemia symptoms and imaging, such as EUS, CT, MRI, and functional imaging. Exendin-4 PET/CT (and SPECT/CT) is a new prominent radiotracer developed to image insulinomas. The aim of the study is to evaluate whether exendin-4 imaging is a useful tool in imaging for insulinoma patients when other imaging methods do not reach them. METHODS: MEDLINE research conducted on PubMed, Scopus, and Web of Science gathered a total of 501 papers. Studies that evaluated exendin-4 SPECT and PET in insulinoma patients were screened and assessed through QUADAS-2 for risk of bias and applicability concerns' assessment. Sensitivity, specificity, and accuracy were reported when available. RESULTS: A total of 13 studies were deemed eligible for a QUADAS 2 review. Studies included ranged from 2009 to 2022. The most-used tracer was 68Ga-DOTA-exendin-4 in PET and 111In-DTPA-exendin-4 in SPECT. Exendin-4 labeled with 99mTc was also reported. The QUADAS-2 risk of bias assessment was overall low, with some unclear reports in the reference and index domains. Only two domains were at high risk of bias because of an explicated non-blind imaging review. Applicability concerns for bias were low in all domains. Reported sensitivities ranged from 95% to 100% and specificities from 20% to 100%. CONCLUSIONS: exendin-4 imaging is a sensitive functional imaging tracer in both SPECT and PET applications, especially in suspicion of benign insulinomas located where endoscopic ultrasound cannot reach, being more sensitive than morfostructural imaging.

PET Criteria by Cancer Type from Imaging Interpretation to Treatment Response Assessment: Beyond FDG PET Score.

BACKGROUND: in recent years, the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) has emerged as a reliable diagnostic tool in a wide variety of pathological conditions. This review aims to collect and review PET criteria developed for interpretation and treatment response assessment in cases of non-[18F]fluorodeoxyglucose ([18F]FDG) imaging in oncology. METHODS: A wide literature search of the PubMed/MEDLINE, Scopus and Google Scholar databases was made to find relevant published articles about non-[18F]FDG PET response criteria. RESULTS: The comprehensive computer literature search revealed 183 articles. On reviewing the titles and abstracts, 149 articles were excluded because the reported data were not within the field of interest. Finally, 34 articles were selected and retrieved in full-text versions. CONCLUSIONS: available criteria are a promising tool for the interpretation of non-FDG PET scans, but also to assess the response to therapy and therefore to predict the prognosis. However, oriented clinical trials are needed to clearly evaluate their impact on patient management.

PET Imaging of Neuro-Inflammation with Tracers Targeting the Translocator Protein (TSPO), a Systematic Review: From Bench to Bedside.

Parkinson's disease is the second most common neurodegenerative disorder, affecting 2-3% of the population of patients >65 years. Although the standard diagnosis of PD is clinical, neuroimaging plays a key role in the evaluation of patients who present symptoms related to neurodegenerative disorders. MRI, DAT-SPECT, and PET with [18F]-FDG are routinely used in the diagnosis and focus on the investigation of morphological changes, nigrostriatal degeneration or shifts in glucose metabolism in patients with parkinsonian syndromes. The aim of this study is to review the current PET radiotracers targeting TSPO, a transmembrane protein that is overexpressed by microglia in another pathophysiological process associated with neurodegenerative disorders known as neuroinflammation. To the best of our knowledge, neuroinflammation is present not only in PD but in many other neurodegenerative disorders, including AD, DLB, and MSA, as well as atypical parkinsonian syndromes. Therefore, in this study, specific patterns of microglial activation in PD and the differences in distribution volumes of these radiotracers in patients with PD as compared to other neurodegenerative disorders are reviewed.

Radiolabeled Dendrimer Coated Nanoparticles for Radionuclide Imaging and Therapy: A Systematic Review.

BACKGROUND: Dendrimers are nanoscale-size polymers with a globular structure. They are composed of an internal core and branching dendrons with surface active groups which can be functionalized for medical applications. Different complexes have been developed for imaging and therapeutic purposes. This systematic review aims to summarize the development of newer dendrimers for oncological applications in nuclear medicine. METHODS: An online literature search was conducted on Pubmed, Scopus, Medline, Cochrane Library, and Web Of Science databases selecting published studies from January 1999 to December 2022. The accepted studies considered the synthesis of dendrimer complexes for oncological nuclear medicine imaging and therapy. RESULTS: 111 articles were identified; 69 articles were excluded because they did not satisfy the selection criteria. Thus, nine duplicate records were removed. The remaining 33 articles were included and selected for quality assessment. CONCLUSION: Nanomedicine has led researchers to create novel nanocarriers with high affinity for the target. Dendrimers represent feasible imaging probes and therapeutic agents since, through the functionalization of external chemical groups and thanks to the possibility to carry pharmaceuticals, it can be possible to exploit different therapeutic strategies and develop a useful weapon for oncological treatments.

Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics-Where We Are at and Where We Are Heading: A Systematic Review.

Cancer is the leading cause of death around the globe, followed by heart disease and stroke, with the highest mortality to this day. We have reached great levels of understanding of how these various types of cancer operate at a cellular level and this has brought us to what we call "precision medicine" where every diagnostic examination and the therapeutic procedure is tailored to the patient. FAPI is among the new tracers that can be used to assess and treat many types of cancer. The aim of this review was to gather all the known literature on FAPI theranostics. A MEDLINE search was conducted on four web libraries, PUBMED, Cochrane, Scopus, and Web of Sciences. All of the available articles that included both diagnoses and therapy with FAPI tracers were collected and put through the CASP (Critical Appraisal Skills Programme) questionnaire for systematic reviewing. A total of 8 records were deemed suitable for CASP review, ranging from 2018 to November 2022. These studies were put through the CASP diagnostic checklist, in order to assess the goal of the study, diagnostic and reference tests, results, descriptions of the patient sample, and future applications. Sample sizes were heterogeneous, both for size as well as for tumor type. Only one author studied a single type of cancer with FAPI tracers. Progression of disease was the most common outcome, and no relevant collateral effects were noted. Although FAPI theranostics is still in its infancy and lacks solid grounds to be brought into clinical practice, it does not show any collateral effects that prohibit administration to patients, thus far, and has good tolerability profiles.

Gastrin-releasing peptide receptor agonists and antagonists for molecular imaging of breast and prostate cancer: from pre-clinical studies to translational perspectives.

INTRODUCTION: Prostate and breast cancer represent a leading cause of cancer-related death worldwide with a dramatic social and demographic impact. Gastrin-releasing peptide receptors (GRPRs), part of the bombesin (BBN) family, have been found overexpressed in both the aforementioned malignancies, and have emerged as a potentially useful target to combine imaging and therapy in a unique, synergistic approach, namely 'theranostics.' AREAS COVERED: The biological characteristics of GRPRs, as well as their aberrant expression in breast and prostate cancer, are covered. Furthermore, the role of the different available GRPR agonists and antagonists, labeled with radionuclides suitable for molecular imaging through single photon computed tomography (SPECT) or positron emission computed (PET/CT), is reviewed, with a particular focus on the potential theranostic implications. EXPERT OPINION: GRPR-targeted molecular imaging of breast and prostate cancer gave promising results in pre-clinical studies. Notably, GRPRs' expression was found to be inversely correlated with disease progression in both prostate and breast cancer. Among the different GRPR agonists and antagonists applied as imaging probes, RM26 presented particularly interesting applications, with meaningful theranostic potential, but its diagnostic performance resulted highly influenced by the choice of the chelator-radionuclide complex, being long-life radionuclides more suitable for obtaining high-contrast imaging.