PARP-Targeted Radiotheranostics with Auger Electrons: An Updated Overview.

Auger electrons (AEs) represent an intriguing topic in the field of radionuclide therapy. They are emitted by several radionuclides commonly used in nuclear medicine (indium-111, iodine-123, iodine-125), allowing for highly localized energy deposition and thus exerting a radiotoxic effect on specific cellular and sub-cellular targets. However, due to their short range in matter, AEs have had limited use in therapeutic applications so far. In recent years, the synthesis of various radiopharmaceuticals capable of binding to the enzyme poly(ADP-ribose) polymerase 1 has reignited interest in this type of therapy, laying the groundwork for a theranostic approach based on radionuclides emitting AEs. The enzyme PARP-1 operates enzymatically in close proximity to DNA that represents the prime target of radionuclide therapies. Following this trend, several PARP-targeted radiopharmaceuticals for AE-based theranostics have been developed. We provide an updated overview of preclinical studies focused on the applications of this new theranostic approach in glioblastoma, breast, prostate and ovarian carcinoma, and pancreatic adenocarcinoma.

The impact of PET imaging on triple negative breast cancer: an updated evidence-based perspective.

INTRODUCTION: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors. It predominantly affects younger women and is associated with a poor prognosis. This systematic review aims to evaluate the current role of positron emission tomography (PET) in the management of TNBC patients and to identify future research directions. METHODS: We systematically searched the PubMed, Scopus, and Web of Science databases up to February 2024. A team of five researchers conducted data extraction and analysis. The quality of the selected studies was assessed using a specific evaluation form. RESULTS: Twenty-eight studies involving 2870 TNBC patients were included in the review. Key clinical applications of PET in TNBC included predicting pathological complete response (pCR) in patients undergoing neoadjuvant chemotherapy (NAC), assessing the prognostic value of baseline PET, and initial disease staging. Two studies utilized PSMA-ligand agents, while the majority used [18F]FDG-based PET. Significant associations were found between baseline [18F]FDG uptake and molecular biomarkers such as PDL-1, androgen receptor, and Ki67. Baseline [18F]FDG PET led to the upstaging of patients from stage IIB to stage IV, influencing treatment decisions and survival outcomes. In the NAC setting, serial PET scans measuring changes in [18F]FDG uptake, indicated by maximum standardized uptake value (SUVmax), predicted pCR with varying cut-off values correlated with different response rates. Semiquantitative parameters such as metabolic tumor volume (MTV) and PET lung index were prognostic for metastatic disease. CONCLUSIONS: In TNBC patients, [18F]FDG PET is essential for initial disease staging in both localized and metastatic settings. It is also useful for assessing treatment response to NAC. The ability of PET to correlate metabolic activity with molecular markers and predict treatment outcomes highlights its potential in TNBC management. Further prospective studies are needed to refine these clinical indications and establish its definitive role.

One Fell Swoop: Septic Muscle Embolism and Central Venous Catheter Infection Imaged with [18F] Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

We describe the case of a 43-year-old female with hereditary hemochromatosis, previously without cardiac issues, who presented with a severe fever (>40 to 41 °C) to our hospital. Initial assessments, including transthoracic echocardiography, showed no typical signs of infective endocarditis. A contrast-enhanced CT scan revealed a hypodense area in the right subscapular muscle, alongside pleural thicknesses. Due to the critical condition, a central venous catheter (CVC) was implanted for immediate intravenous treatment. Subsequent blood cultures, positive for Staphylococcus aureus, and transesophageal echocardiography led to a diagnosis of multivalvular infective endocarditis (MIE). Subsequently, the patient underwent positron emission tomography/computed tomography (PET/CT) with [18F]Fluorodeoxyglucose ([18F]FDG), which detected increased tracer incorporation in the muscle lesion, CVC, and pleural thicknesses. The final diagnosis was CVC infection and septic embolism to the subscapular muscle in a patient with pleuritis. This case showcases the critical role of [18F]FDG PET/CT as whole-body imaging modality in diagnosing and managing complex infective cases.

A promising case of preclinical-clinical translation: ß-adrenoceptor blockade from the oxygen-induced retinopathy model to retinopathy of prematurity.

Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus hindering drug development for eye diseases. In particular, angiogenesis-related retinal diseases share common mechanisms and are responsible for the majority of cases of blindness. Their prevalence is globally increasing mostly because of the increased incidence of systemic pathologies in the adult. Despite the number of preclinical findings demonstrating the efficacy of novel treatments, therapy of retinal neovascular diseases still remains confined to intravitreal anti-vascular endothelial growth factor treatments with some extension to anti-inflammatory therapy. In the mare magnum of preclinical findings aimed to develop novel avenues for future therapies, most compounds, despite their efficacy in experimental models, do not seem to meet the criteria for their therapeutic application. In particular, the groove between preclinical findings and their clinical application increases instead of decreasing and the attempt to bridging the gap between them creates intense frustration and a sense of defeat. In this complex scenario, we will discuss here the role that overactivation of the sympathetic system plays in retinal vessel proliferation in response to hypoxia using the oxygen-induced retinopathy (OIR) model. The potential application of the beta-adrenoceptor (ß-AR) blockade with propranolol to the treatment of retinopathy of prematurity will be also discussed in light of preclinical findings in the OIR model and clinical trials using propranolol in preterm infants either per os or as eye drops.

Positron emission computed tomography targeting urokinase plasminogen activator receptor (uPAR) in cancer: a systematic review.

INTRODUCTION: To provide an overview of the available literature data on clinical applications of positron emission tomography (PET) targeting the urokinase-type plasminogen activator receptor in oncology. METHODS: A literature search was conducted in PubMed, Web of Science and Scopus databases up to June 2023. The results were presented according to the PRISMA guidelines. The quality of the studies was assessed using the Critical Appraisal Skill Program checklist. RESULTS: Seven papers were selected for final analysis, involving 266 patients with solid tumors who underwent PET with uPAR-ligands. Thematic areas identified include feasibility studies (n = 2) on the safety, pharmacokinetics, and dosimetry of uPAR-targeting radiopharmaceuticals; uPAR-directed imaging in head and neck cancer (n = 2); uPAR PET in prostate cancer (n = 2); and the investigation of uPAR in neuroendocrine neoplasms (n = 1). Six of the seven studies used the radiopharmaceutical [68Ga]Ga-NOTA-AE105 while one study used [64Cu]Cu-DOTA-AE105. The studies showed protocol homogeneity, with static PET imaging at 20 minutes. The quality assessment revealed limitations such as small cohorts and the fact that all studies were performed by a single research group. CONCLUSIONS: uPAR-PET appears to be a promising imaging tool in well-selected oncological settings, but it needs to be validated by multicentre collaboration.

99mTc-labeled FAPI compounds for cancer and inflammation: from radiochemistry to the first clinical applications.

BACKGROUND: In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation. However, PET represents a high-cost technology, and its widespread adoption is still limited compared to the availability of gamma cameras. To address this issue, several efforts have been made to explore the potential of [99mTc]Tc-FAPi tracers as molecular probes for imaging with gamma cameras and single photon emission computed tomography (SPECT). MAIN BODY: Several approaches have been investigated for labeling FAPi-based compounds with 99mTc. Specifically, the mono-oxo, tricarbonyl, isonitrile, and HYNIC strategies have been applied to produce [99mTc]Tc-FAPi tracers, which have been tested in vitro and in animal models. Overall, these labeling approaches have demonstrated high efficiency and strong binding. The resulting [99mTc]Tc-FAPi tracers have shown high specificity for FAP-positive cells and xenografts in both in vitro and animal model studies, respectively. However, the majority of [99mTc]Tc-FAPi tracers have exhibited variable levels of lipophilicity, leading to preferential excretion through the hepatobiliary route and undesirable binding to lipoproteins. Consequently, efforts have been made to synthesize more hydrophilic FAPi-based compounds to improve pharmacokinetic properties and achieve a more favorable biodistribution, particularly in the abdominal region. SPECT imaging with [99mTc]Tc-FAPi has yielded promising results in patients with gastrointestinal tumors, demonstrating comparable or superior diagnostic performance compared to other imaging modalities. Similarly, encouraging outcomes have been observed in subjects with gliomas, lung cancer, breast cancer, and cervical cancer. Beyond oncological applications, [99mTc]Tc-FAPi-based imaging has been successfully employed in myocardial and idiopathic pulmonary fibrosis. CONCLUSIONS: This overview focuses on the various radiochemical strategies for obtaining [99mTc]Tc-FAPi tracers, highlighting the main challenges encountered and possible solutions when applying each distinct approach. Additionally, it covers the preclinical and initial clinical applications of [99mTc]Tc-FAPi in cancer and inflammation.

18F-FDG PET-CT Scans in Oncology Patients Treated with Hyaluronic Acid Filler: Not Always a Pitfall.

The use of hyaluronic acid (HA) fillers in oncology patients undergoing PET-CT scans is a topic of debate due to potential interference with imaging accuracy. A 54-year-old female, postmelanoma metastasectomy in the parotid region with subsequent facial nerve palsy (FNP), received HA filler injections for facial symmetry and functional restoration. Follow-up PET-CT scans showed no interference or artifacts attributable to HA injection, allowing for accurate imaging results. This case suggests that HA fillers administered in oncology patients may not universally pose challenges or disrupt PET-CT imaging interpretation. Due to the possible false positives induced by fillers, the inclusion of aesthetic treatments in patients' anamnesis is a crucial step to accurately interpret PET-CT images. Although maintaining high level of caution in interpreting PET-CT results after filler injection is essential, our case emphasizes the safety of this procedure in oncology patients undergoing follow-up PET-CT scans.

Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression.

Despite the evident progress in neonatal medicine, retinopathy of prematurity (ROP) remains a serious threat to the vision of premature infants, due to a still partial understanding of the mechanisms underlying the development of this disease and the lack of drugs capable of arresting its progression. Although ROP is a multifactorial disease, retinal vascularization is strictly dependent on oxygen concentration. The exposition of the retina of a preterm newborn, still incompletely vascularized, to an atmosphere relatively hyperoxic, as the extrauterine environment, induces the downregulation of proangiogenic factors and therefore the interruption of vascularization (first ischemic phase of ROP). However, over the following weeks, the growing metabolic requirement of this ischemic retina produces a progressive hypoxia that specularly promotes the surge of proangiogenic factors, finally leading to proliferative retinopathy (second proliferative phase of ROP). The demonstration that the noradrenergic system is actively involved in the coupling between hypoxia and the induction of vasculogenesis paved the way for a pharmacologic intervention aimed at counteracting the interaction of noradrenaline with specific receptors and consequently the progression of ROP. A similar trend has been observed in infantile hemangiomas, the most common vascular lesion of childhood induced by pre-existing hypoxia, which shares similar characteristics with ROP. The fact that propranolol, an unselective antagonist of ß1/2 adrenoceptors, counteracts the growth of infantile hemangiomas, suggested the idea of testing the efficacy of propranolol in infants with ROP. From preclinical studies, ongoing clinical trials demonstrated that topical administration of propranolol likely represents the optimal approach to reconcile its efficacy and maximum safety. Given the strict relationship between vessels and neurons, recovering retinal vascularization with propranolol may add further efficacy to prevent retinal dysfunction. In conclusion, the strategy of contrasting precociously the progression of the disease appears to be more advantageous than the current wait-and-see therapeutic approach, which instead is mainly focused on avoiding retinal detachment.

Implementation of Listening Visits with Parents of Preterm Infants in an Italian Neonatal Intensive Care Unit.

PURPOSE: To assess the feasibility of implementing Listening Visits (LV) in an Italian neonatal intensive care unit (NICU). STUDY DESIGN AND METHODS: This feasibility implementation of LV included empathic listening and problem-solving sessions provided by a psychologist to 26 parents of hospitalized preterm newborns. Using the RE-AIM implementation framework, three facets of feasibility were assessed: reach, adoption, and implementation. RESULTS: It is feasible to integrate LV into the NICU: 76% of families were willing to try LV (reach). Listening Visits recipients reported high satisfaction. Twelve of the 16 families (75%) received six or more LV sessions (adoption), with mothers attending more sessions. Implementation fidelity, defined here as the percentage of LV recipients that received at least four sessions, was 94% among mothers and 30% among fathers. CLINICAL IMPLICATIONS: The LV intervention for parental support during the NICU stay is feasible and deemed helpful by parents. Parents were motivated to participate even though their levels of depression, stress, and anxiety were not high. In addition to the use of standardized screening questionnaires, parental requests and clinical team indications should be included in the decision-making for the provision of parental support services.

ß3-adREnoceptor Analysis in CORD Blood of Neonates (ß3 RECORD): Study Protocol of a Pilot Clinical Investigation.

Background and Objective: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the ß-adrenergic system. In animals, ß3-adrenoceptors (ß3-ARs), up-regulated by hypoxia, favor global fetal wellness to such an extent that most diseases related to prematurity are hypothesized to be induced or aggravated by a precocious ß3-AR down-regulation, due to premature exposure to a relatively hyperoxic environment. In animals, ß3-AR pharmacological agonism is currently investigated as a possible new therapeutic opportunity to counteract oxygen-induced damages. Our goal is to translate the knowledge acquired in animals to humans. Recently, we have demonstrated that fetuses become progressively more hypoxemic from mid-gestation to near-term, but starting from the 33rd-34th week, oxygenation progressively increases until birth. The present paper aims to describe a clinical research protocol, evaluating whether the expression level of HIF-1, ß3-ARs, and VEGF is modulated by oxygen during intrauterine and postnatal life, in a similar way to animals. Materials and Methods: In a prospective, non-profit, single-center observational study we will enroll 100 preterm (group A) and 100 full-term newborns (group B). We will collect cord blood samples (T0) and measure the RNA expression level of HIF-1, ß3-ARs, and VEGF by digital PCR. In preterms, we will also measure gene expression at 48-72h (T1), 14 days (T2), and 30 days (T3) of life and at 40 ± 3 weeks of post-menstrual age (T4), regardless of the day of life. We will compare group A (T0) vs. group B (T0) and identify any correlations between the values obtained from serial samples in group A and the clinical data of the patients. Our protocol has been approved by the Pediatric Ethical Committee for Clinical Research of the Tuscany region (number 291/2022). Expected Results: The observation that in infants, the HIF-1/ß3-ARs/VEGF axis shows similar modulation to that of animals could suggest that ß3-ARs also promote fetal well-being in humans.

Protective Effects of Beta-3 Adrenoceptor Agonism on Mucosal Integrity in Hyperoxia-Induced Ileal Alterations.

Organogenesis occurs in the uterus under low oxygen levels (4%). Preterm birth exposes immature newborns to a hyperoxic environment, which can induce a massive production of reactive oxygen species and potentially affect organ development, leading to diseases such as necrotizing enterocolitis. The ß3-adrenoreceptor (ß3-AR) has an oxygen-dependent regulatory mechanism, and its activation exerts an antioxidant effect. To test the hypothesis that ß3-AR could protect postnatal ileal development from the negative impact of high oxygen levels, Sprague-Dawley rat pups were raised under normoxia (21%) or hyperoxia (85%) for the first 2 weeks after birth and treated or not with BRL37344, a selective ß3-AR agonist, at 1, 3, or 6 mg/kg. Hyperoxia alters ileal mucosal morphology, leading to increased cell lipid oxidation byproducts, reduced presence of ß3-AR-positive resident cells, decreased junctional protein expression, disrupted brush border, mucin over-production, and impaired vascularization. Treatment with 3 mg/kg of BRL37344 prevented these alterations, although not completely, while the lower 1 mg/kg dose was ineffective, and the higher 6 mg/kg dose was toxic. Our findings indicate the potential of ß3-AR agonism as a new therapeutic approach to counteract the hyperoxia-induced ileal alterations and, more generally, the disorders of prematurity related to supra-physiologic oxygen exposure.

Innovations in Positron Emission Tomography and State of the Art in the Evaluation of Breast Cancer Treatment Response.

The advent of hybrid Positron Emission Tomography/Computed Tomography (PET/CT) and PET/Magnetic Resonance Imaging (MRI) scanners resulted in an increased clinical relevance of nuclear medicine in oncology. The use of [18F]-Fluorodeoxyglucose ([18F]FDG) has also made it possible to study tumors (including breast cancer) from not only a dimensional perspective but also from a metabolic point of view. In particular, the use of [18F]FDG PET allowed early confirmation of the efficacy or failure of therapy. The purpose of this review was to assess the literature concerning the response to various therapies for different subtypes of breast cancer through PET. We start by summarizing studies that investigate the validation of PET/CT for the assessment of the response to therapy in breast cancer; then, we present studies that compare PET imaging (including PET devices dedicated to the breast) with CT and MRI, focusing on the identification of the most useful parameters obtainable from PET/CT. We also focus on novel non-FDG radiotracers, as they allow for the acquisition of information on specific aspects of the new therapies.

ß3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations.

Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not completely develop in utero. The ß3-adrenoreceptor (ß3-AR) is expressed in the colon and has an oxygen-dependent regulatory mechanism. This study shows the effects of the ß3-AR agonist BRL37344 in a neonatal model of hyperoxia-driven colonic injury. For the first 14 days after birth, Sprague-Dawley rat pups were exposed to ambient oxygen levels (21%) or hyperoxia (85%) and treated daily with BRL37344 at 1, 3, 6 mg/kg or untreated. At the end of day 14, proximal colon samples were collected for analysis. Hyperoxia deeply influences the proximal colon development by reducing ß3-AR-expressing cells (27%), colonic length (26%) and mucin production (47%), and altering the neuronal chemical coding in the myenteric plexus without changes in the neuron number. The administration of BRL37344 at 3 mg/kg, but not at 1 mg/kg, significantly prevented these alterations. Conversely, it was ineffective in preventing hyperoxia-induced body weight loss. BRL37344 at 6 mg/kg was toxic. These findings pave the way for ß3-AR pharmacological targeting as a therapeutic option for diseases caused by hyperoxia-impaired development, typical prematurity disorders.