In the last decades, the development of PET/CT radiopharmaceuticals, targeting the Prostate-Specific Membrane Antigen (PSMA), changed the management of prostate cancer (PCa) patients thanks to its higher diagnostic accuracy in comparison with conventional imaging both in staging and in recurrence. Alongside molecular imaging, PSMA was studied as a therapeutic agent targeted with various isotopes. In 2021, results from the VISION trial led to the Food and Drug Administration (FDA) approval of [¹⁷⁷Lu]Lu-PSMA-617 as a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) and set the basis for a radical change in the future perspectives of PCa treatment and the history of Nuclear Medicine. Despite these promising results, primary resistance in patients treated with single-agent [¹⁷⁷Lu]Lu-PSMA-617 remains a real issue. Emerging trials are investigating the use of [¹⁷⁷Lu]Lu-PSMA-617 in combination with other PCa therapies in order to cover the multiple oncologic resistance pathways and to overcome tumor heterogeneity. In this review, our aim is to retrace the history of PSMA-targeted therapy from the first preclinical studies to its future applications in PCa.

Background: To investigate the cause of lymphopenia in patients with newly diagnosed COVID-19, we measured [¹⁸F]FDG uptake in several tissues, including the ileum, right colon, and caecum at diagnosis and after recovery and correlated these measurements with haematological parameters. Methods: We studied, by [¹⁸F]FDG PET/CT, 18 newly diagnosed patients with COVID-19. Regions of interest were drawn over major organs and in the terminal ileum, caecum, and right colon, where the bowel wall was evaluable. Five patients were re-examined after recovery, and three of them also performed a white blood cell scan with ^99mTc-HMPAO-WBC on both occasions. Complete blood count was performed on both occasions, and peripheral blood lymphocyte subsets were measured at diagnosis. Data were analysed by a statistician. Results: Patients had moderate severity COVID-19 syndrome. Basal [¹⁸F]FDG PET/CT showed focal lung uptake corresponding to hyperdense areas at CT. We also found high spleen, ileal, caecal, and colonic activity as compared to 18 control subjects. At recovery, hypermetabolic tissues tended to normalize, but activity in the caecum remained higher than in controls. Regression analyses showed an inverse correlation between CD4 + lymphocytes and [¹⁸F]FDG uptake in the caecum and colon and a direct correlation between CD8 + lymphocytes and [¹⁸F]FDG uptake in lungs and bone marrow. WBC scans showed the presence of leukocytes in the caecum and colon that disappeared at recovery. Conclusions: These findings indicate that lymphopenia in COVID-19 patients is associated with large bowel inflammation supporting the hypothesis that CD4 + lymphocytes migrate to peripheral lymphoid tissues in the bowel.

Background: Since most endocrine glands express ACE-2 receptors and can be infected by SARS-CoV-2 virus, this retrospective multicentre observational study aims to assess the metabolic activity of thyroid and adrenal glands of COVID-19 patients by ¹⁸F-FDG PET/CT. Methods: We retrospectively evaluated the ¹⁸F-FDG PET/CT scans of COVID-19 patients admitted by three different centres, either in a low-intensity department or in the intensive care unit (ICU). A visual assessment and a semi-quantitative evaluation of areas of interest in thyroid and adrenal glands were performed by recording SUVmax and SUVmean. The ¹⁸F-FDG PET/CT uptake in COVID-19 patients was compared with those observed in normal age-matched controls. Results: Between March 2020 and March 2022, 33 patients from three different centres (twenty-eight patients in a low-intensity department and five patients in ICU), were studied by ¹⁸F-FDG PET/CT during active illness. Seven of them were also studied after clinical remission (3–6 months after disease onset). Thirty-six normal subjects were used as age-matched controls. In the thyroid gland, no statistically significant differences were observed between control subjects and COVID-19 patients at diagnosis. However, at the follow-up PET/CT study, we found a statistically higher SUVmax and SUVmean (p = 0.009 and p = 0.004, respectively) in the thyroid of COVID-19 patients. In adrenal glands, we observed lower SUVmax and SUVmean in COVID-19 patients at baseline compared to control subjects (p < 0.0001) and this finding did not normalize after clinical recovery (p = 0.0018 for SUVmax and p = 0.002 for SUV mean). Conclusions: In our series, we observed persistent low ¹⁸F-FDG uptake in adrenal glands of patients at diagnosis of COVID-19 and after recovery, suggesting a chronic hypofunction. By contrast, thyroid uptake was comparable to normal subjects at disease onset, but after recovery, a subgroup of patients showed an increased metabolism, thus possibly suggesting the onset of an inflammatory thyroiditis. Our results should alert clinicians to investigate the pituitary–adrenal axis and thyroid functionality at the time of infection and to monitor them after recovery.

Grade 3 (G3) neuroendocrine tumors (NETs) are a novel category among digestive neuroendocrine neoplasms, characterized by Ki-67 >20% and a well-differentiated morphology, presenting high intra-tumor heterogeneity. We aimed to explore the role of dual-tracer PET imaging (⁶⁸Gallium (Ga)-DOTATOC and ¹⁸Fluorodeoxyglucose (FDG)) as overall survival (OS) predictor in NET G3 patients. We performed a retrospective analysis in NET G3 patients treated at our institution between 2003 and 2021. Accordingly, 30 NET G3 patients were analyzed. ⁶⁸Ga-DOTA-TOC and ¹⁸F-FDG uptake were assessed by tumor/non-tumor (T-nonT) ratio. We reported a slightly better OS for patients with ≥75% concordance between ⁶⁸Ga-DOTA-TOC and ¹⁸F-FDG PET/CT (p = 0.42). Among patients with discordant functional imaging, we reported a better 5-y OS rate for patients with a prevalent ⁶⁸Ga-DOTATOC vs. ¹⁸F-FDG PET/CT (p = 0.016). In positive ¹⁸F-FDG PET/CT cases, we reported a better OS for <4 vs. ≥4 T/non-T ratio (p = 0.021). Among upfront-NET G3 patients with concordant exams, 5-y OS rate was 83.3% (95% CI: 27.3–97.5). Among patients with discordant exams, 5-y OS rate was 81.3% (52.5–93.5), 100% for those with prevalent receptor expression, and 50% (11.1–80.4) for those with prevalent ¹⁸F-FDG uptake. Our findings suggest that dual-tracer PET/CT can be considered as a predictor of patient outcome, able to stratify NET G3 patients with poorer prognosis.