Empowering PET: harnessing deep learning for improved clinical insight.

This review aims to take a journey into the transformative impact of artificial intelligence (AI) on positron emission tomography (PET) imaging. To this scope, a broad overview of AI applications in the field of nuclear medicine and a thorough exploration of deep learning (DL) implementations in cancer diagnosis and therapy through PET imaging will be presented. We firstly describe the behind-the-scenes use of AI for image generation, including acquisition (event positioning, noise reduction though time-of-flight estimation and scatter correction), reconstruction (data-driven and model-driven approaches), restoration (supervised and unsupervised methods), and motion correction. Thereafter, we outline the integration of AI into clinical practice through the applications to segmentation, detection and classification, quantification, treatment planning, dosimetry, and radiomics/radiogenomics combined to tumour biological characteristics. Thus, this review seeks to showcase the overarching transformation of the field, ultimately leading to tangible improvements in patient treatment and response assessment. Finally, limitations and ethical considerations of the AI application to PET imaging and future directions of multimodal data mining in this discipline will be briefly discussed, including pressing challenges to the adoption of AI in molecular imaging such as the access to and interoperability of huge amount of data as well as the "black-box" problem, contributing to the ongoing dialogue on the transformative potential of AI in nuclear medicine.Relevance statementAI is rapidly revolutionising the world of medicine, including the fields of radiology and nuclear medicine. In the near future, AI will be used to support healthcare professionals. These advances will lead to improvements in diagnosis, in the assessment of response to treatment, in clinical decision making and in patient management.Key points• Applying AI has the potential to enhance the entire PET imaging pipeline.• AI may support several clinical tasks in both PET diagnosis and prognosis.• Interpreting the relationships between imaging and multiomics data will heavily rely on AI.

The potential role of osteoporosis in unspecific [18F]PSMA-1007 bone uptake.

AIM: Unspecific bone uptake is one of the main limitations of PET imaging with some PSMA-targeting radiopharmaceuticals, especially with [18F]PSMA-1007. We explored the potential association between osteoporosis and the occurrence of unspecific [18F]PSMA-1007 bone uptake investigating markers which might correlate with bone mineral density. MATERIALS AND METHODS: We retrospectively analyzed treatment-naïve patients with a confirmed diagnosis of prostate adenocarcinoma who underwent staging [18F]PSMA-1007 positron emission tomography (PET). Qualitative image analysis was performed independently by three experienced nuclear medicine physicians. Patients were divided in two groups according to the presence/absence of unspecific bone uptake. Clinical information, blood count parameters (assessed within 3 months to the PET scan), body mass index (BMI), and bone density as estimated by computed tomography were collected. The Kruskal-Wallis and t-test were used to compare parameters. RESULTS: We analyzed 77 patients: 29 of them (38%) had unspecific bone uptake at [18F]PSMA-1007 PET, most commonly in the pelvic bones (69%) and ribs (62%). We did not find any significant difference in clinical parameters in the two groups. In patients with unspecific bone uptake, white blood cell, and neutrophil counts were significantly higher; in the same group, we observed lower values of BMI and bone density, although not statistically different. CONCLUSIONS: We observed unspecific bone uptake on [18F]PSMA-1007 PET in more than 1/3 of patients. In this exploratory analysis, we found a significant correlation between blood count parameters and unspecific [18F]PSMA-1007 bone uptake. We may speculate that [18F]PSMA-1007 unspecific bone uptake could be associated with osteoporosis. This hypothesis needs to be further investigated in larger populations and exploring more specific markers of osteoporosis.

The prognostic power of [11C]methionine PET in IDH-wildtype diffuse gliomas with lower-grade histological features: venturing beyond WHO classification.

PURPOSE: IDH-wildtype (IDH-wt) diffuse gliomas with histological features of lower-grade gliomas (LGGs) are rare and heterogeneous primary brain tumours. [11C]Methionine (MET) positron emission tomography (PET) is commonly used to evaluate glial neoplasms at diagnosis. The present study aimed to assess the prognostic value of MET PET in newly diagnosed, treatment naïve IDH-wt gliomas with histological features of LGGs. METHODS: Patients with a histological diagnosis of IDH-wt LGG who underwent preoperative (< 100 days) MET PET/CT and surgery were retrospectively included. Qualitative and semi-quantitative analyses of MET PET images were performed. Progression-free survival (PFS) and overall survival (OS) were analysed by Kaplan-Meier curves. Cox proportional-hazards regression was used to test the association of imaging and clinical data to PFS and OS. RESULTS: We included 48 patients (M:F = 25:23; median age 55). 39 lesions were positive and 9 negative at MET PET. Positive MET PET was significantly associated with shorter median PFS (15.7 months vs. not reached, p = 0.0146) and OS time (32.6 months vs. not reached, p = 0.0253). Incomplete surgical resection and higher TBRmean values were independent predictors of shorter PFS on multivariate analysis (p < 0.001 for both). Higher tumour grade and incomplete surgical resection were independent predictors of OS at multivariate analysis (p = 0.027 and p = 0.01, respectively). CONCLUSION: MET PET is useful for the prognostic stratification of patients with IDH-wt glial neoplasms with histological LGGs features. Considering their huge biological heterogeneity, the combination of MET PET and molecular analyses may help to improve the prognostic accuracy in these diffuse gliomas subset and influence therapeutic choices accordingly.

The complementary role of PSMA expression and [18F]FDG PET/CT in predicting thyroid cancer outcome: from black and white to shades of gray, in the era of precision oncology.

BACKGROUND: The value of Prostate Specific Membrane Antigen (PSMA) in thyroid carcinoma (TC) is still unknown. We aimed to test the potential complementary role of PSMA expression and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake on PET/CT as biomarkers for TC outcome prediction. MATERIALS AND METHODS: From a retrospective cohort of TC patients we selected those fulfilling the following inclusion/exclusion criteria: thyroidectomy in our Institution, available primary tumor tissue PSMA immunostaining, [18F]FDG PET/CT and follow-up data. PSMA staining was visually assessed. PET/CT was considered positive in case of [18F]FDG uptake higher than the background at the site of TC confirmed by cyto-/histology, and/or follow-up. Disease recurrence, radioiodine refractoriness (RAI-R) and status at last follow-up (LFU) were used as outcome endpoints. RESULTS: We included 23 subjects. Disease recurrence occurred in 18 patients (median time 11 months, range 1-40); among these 12/18 developed RAI-R (median time 28 months, range 2-221), and 13/18 had evidence of disease at LFU. PSMA expression was negative in 6/23 cases. PET/CT was negative in 11/23 patients (7/11 experienced recurrence). PET/CT was positive in 9/12 patients showing RAI-R and 10/13 cases with evidence of disease at LFU. All patients with positive PET/CT had a positive PSMA immunostaining. Six out of 11 patients with negative PET/CT were positive at immunostaining, showing lower PSMA expression (median score of 30%, range 0-80%) than patients with positive PET/CT. The TC samples without PSMA expression belonged to patients who resulted negative also at PET/CT (3 experienced recurrence, 2 were RAI-R, and 1 had disease at LFU). Four out of 11 patients who resulted negative at PET/CT exhibited very high PSMA expression (≥ 70%) and although 3 of them experienced recurrence, none resulted RAI-R, and only 1 had persistent disease at LFU. CONCLUSIONS: Primary tumor PSMA expression and [18F]FDG uptake seem to play a complementary prognostic role in TC. The majority of patients who expressed PSMA recurred. In the intermediate ATA risk class, patients with negative PSMA immunostaining recurred less than patients expressing PSMA. Additionally, although patients with a negative [18F]FDG PET/CT had a favourable long-term outcome, PSMA assessment might be useful to timely identify subjects at higher risk of recurrence.

Now you see me: lights on Merkel Cell Carcinoma.

Merkel Cell Carcinoma (MCC) is a rare primary cutaneous cancer with aggressive behaviour and poor prognosis. Although MCC cells express somatostatin receptors (SSTR), SSTR-targeted PET/CT is not routinely performed in clinical practice. In contrast, the use of [18F]FDG PET/CT is more widespread and its prognostic role is well established. We present the case of an MCC patient suspected recurrence who underwent restaging with both [18F]FDG and [68 Ga]Ga-DOTA-TOC PET/CT. [18F]FDG PET/CT showed pathological uptake only in mediastinal lymph nodes, but SSTR imaging also revealed multiple liver and skeletal metastases, leading to significant disease upstaging and relevant changes in the therapeutic management.

The Role of PET Imaging in the Differential Diagnosis between Radiation Necrosis and Recurrent Disease in Irradiated Adult-Type Diffuse Gliomas: A Systematic Review.

Adult-type diffuse gliomas are treated with a multimodality treatment approach that includes radiotherapy both in the primary setting, and in the case of progressive or recurrent disease. Radiation necrosis represents a major complication of radiotherapy. Recurrent disease and treatment-related changes are often indistinguishable using conventional imaging methods. The present systematic review aims at assessing the diagnostic role of PET imaging using different radiopharmaceuticals in differentiating radiation necrosis and disease relapse in irradiated adult-type diffuse gliomas. We conducted a comprehensive literature search using the PubMed/MEDLINE and EMBASE databases for original research studies of interest. In total, 436 articles were assessed for eligibility. Ten original papers, published between 2014 and 2022, were selected. Four articles focused on [18F]FDG, seven on amino acid tracers ([18F]FET n = 3 and [11C]MET n = 4), one on [11C]CHO, and one on [68Ga]Ga-PSMA. Visual assessment, semi-quantitative methods, and radiomics were applied for image analysis. Furthermore, 2/10 papers were comparative studies investigating different radiopharmaceuticals. The present review, the first one on the topic in light of the new 2021 CNS WHO classification, highlighted the usefulness of PET imaging in distinguishing radiation necrosis and tumour recurrence, but revealed high heterogeneity among studies.

COVID-19 vaccination, implications for PET/CT image interpretation and future perspectives.

Introduction: The present paper aims to systematically review the literature on COVID-19 vaccine-related findings in patients undergoing PET/CT. Methods: The search algorithms included the following combination of terms: "PET" OR "positron emission tomography" AND "COVID"; "PET" OR "positron emission tomography" AND "COVID" AND "vaccination"; "PET" OR "positron emission tomography" AND "COVID", AND "autoimmune". Results: We selected 17 articles which were assessed for quality and included in the systematic analysis. The most frequent vaccine-related signs on PET/CT were the deltoid [18F]FDG uptake and axillary hypermetabolic lymph nodes, which were described in 8-71% and 7-90% of the patients, respectively. Similarly, frequency of these findings using other tracers than [18F]FDG was greatly variable. This large variability was related to the variability in time elapsed between vaccination and PET/CT, and the criteria used to define positivity. In addition, vaccine-related findings were detected more frequently in young and immunocompetent patients than in elderly and immunocompromised ones. Discussion: Therefore, awareness on vaccination status (timing, patient characteristics, and concurrent therapies) and knowledge on patterns of radiopharmaceutical uptake are necessary to properly interpret PET/CT findings.

Contrast-Enhanced Mammography versus Breast Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis.

BACKGROUND: Contrast-enhanced mammography (CEM) and contrast-enhanced magnetic resonance imaging (CE-MRI) are commonly used in the screening of breast cancer. The present systematic review aimed to summarize, critically analyse, and meta-analyse the available evidence regarding the role of CE-MRI and CEM in the early detection, diagnosis, and preoperative assessment of breast cancer. METHODS: The search was performed on PubMed, Google Scholar, and Web of Science on 28 July 2021 using the following terms "breast cancer", "preoperative staging", "contrast-enhanced mammography", "contrast-enhanced spectral mammography", "contrast enhanced digital mammography", "contrast-enhanced breast magnetic resonance imaging" "CEM", "CESM", "CEDM", and "CE-MRI". We selected only those papers comparing the clinical efficacy of CEM and CE-MRI. The study quality was assessed using the QUADAS-2 criteria. The pooled sensitivities and specificity of CEM and CE-MRI were computed using a random-effects model directly from the STATA "metaprop" command. The between-study statistical heterogeneity was tested (I2-statistics). RESULTS: Nineteen studies were selected for this systematic review. Fifteen studies (1315 patients) were included in the metanalysis. Both CEM and CE-MRI detect breast lesions with a high sensitivity, without a significant difference in performance (97% and 96%, respectively). CONCLUSIONS: Our findings confirm the potential of CEM as a supplemental screening imaging modality, even for intermediate-risk women, including females with dense breasts and a history of breast cancer.

Preoperative [11C]methionine PET to personalize treatment decisions in patients with lower-grade gliomas.

BACKGROUND: PET with radiolabeled amino acids is used in the preoperative evaluation of patients with glial neoplasms. This study aimed to assess the role of [11C]methionine (MET) PET in assessing molecular features, tumor extent, and prognosis in newly diagnosed lower-grade gliomas (LGGs) surgically treated. METHODS: One hundred and fifty-three patients with a new diagnosis of grade 2/3 glioma who underwent surgery at our Institution and were imaged preoperatively using [11C]MET PET/CT were retrospectively included. [11C]MET PET images were qualitatively and semi-quantitatively analyzed using tumor-to-background ratio (TBR). Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and Cox proportional-hazards regression was used to test the association of clinicopathological and imaging data to PFS. RESULTS: Overall, 111 lesions (73%) were positive, while thirty-two (21%) and ten (6%) were isometabolic and hypometabolic at [11C]MET PET, respectively. [11C]MET uptake was more common in oligodendrogliomas than IDH-mutant astrocytomas (87% vs 50% of cases, respectively). Among [11C]MET-positive gliomas, grade 3 oligodendrogliomas had the highest median TBRmax (3.22). In 25% of patients, PET helped to better delineate tumor margins compared to MRI only. In IDH-mutant astrocytomas, higher TBRmax values at [11C]MET PET were independent predictors of shorter PFS. CONCLUSIONS: This work highlights the role of preoperative [11C]MET PET in estimating the type of suspected LGGs, assessing tumor extent, and predicting biological behavior and prognosis of histologically confirmed LGGs. Our findings support the implementation of [11C]MET PET in routine clinical practice to better manage these neoplasms.

State-of-the-art of FAPI-PET imaging: a systematic review and meta-analysis.

INTRODUCTION: Fibroblast activation protein-α (FAPα) is overexpressed on cancer-associated fibroblasts in approximately 90% of epithelial neoplasms, representing an appealing target for therapeutic and molecular imaging applications. [68 Ga]Ga-labelled radiopharmaceuticals-FAP-inhibitors (FAPI)-have been developed for PET. We systematically reviewed and meta-analysed published literature to provide an overview of its clinical role. MATERIALS AND METHODS: The search, limited to January 1st, 2018-March 31st, 2021, was performed on MedLine and Embase databases using all the possible combinations of terms "FAP", "FAPI", "PET/CT", "positron emission tomography", "fibroblast", "cancer-associated fibroblasts", "CAF", "molecular imaging", and "fibroblast imaging". Study quality was assessed using the QUADAS-2 criteria. Patient-based and lesion-based pooled sensitivities/specificities of FAPI PET were computed using a random-effects model directly from the STATA "metaprop" command. Between-study statistical heterogeneity was tested (I2-statistics). RESULTS: Twenty-three studies were selected for systematic review. Investigations on staging or restaging head and neck cancer (n = 2, 29 patients), abdominal malignancies (n = 6, 171 patients), various cancers (n = 2, 143 patients), and radiation treatment planning (n = 4, 56 patients) were included in the meta-analysis. On patient-based analysis, pooled sensitivity was 0.99 (95% CI 0.97-1.00) with negligible heterogeneity; pooled specificity was 0.87 (95% CI 0.62-1.00), with negligible heterogeneity. On lesion-based analysis, sensitivity and specificity had high heterogeneity (I2 = 88.56% and I2 = 97.20%, respectively). Pooled sensitivity for the primary tumour was 1.00 (95% CI 0.98-1.00) with negligible heterogeneity. Pooled sensitivity/specificity of nodal metastases had high heterogeneity (I2 = 89.18% and I2 = 95.74%, respectively). Pooled sensitivity in distant metastases was good (0.93 with 95% CI 0.88-0.97) with negligible heterogeneity. CONCLUSIONS: FAPI-PET appears promising, especially in imaging cancers unsuitable for [18F]FDG imaging, particularly primary lesions and distant metastases. However, high-level evidence is needed to define its role, specifically to identify cancer types, non-oncological diseases, and clinical settings for its applications.

Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study.

PURPOSE: The present study hypothesised that whole-body [18F]FDG-PET/CT might provide insight into the pathophysiology of long COVID. METHODS: We prospectively enrolled 13 adult long COVID patients who complained for at least one persistent symptom for >30 days after infection recovery. A group of 26 melanoma patients with negative PET/CT matched for sex/age was used as controls (2:1 control to case ratio). Qualitative and semi-quantitative analysis of whole-body images was performed. Fisher exact and Mann-Whitney tests were applied to test differences between the two groups. Voxel-based analysis was performed to compare brain metabolism in cases and controls. Cases were further grouped according to prevalent symptoms and analysed accordingly. RESULTS: In 4/13 long COVID patients, CT images showed lung abnormalities presenting mild [18F]FDG uptake. Many healthy organs/parenchyma SUVs and SUV ratios significantly differed between the two groups (p ≤ 0.05). Long COVID patients exhibited brain hypometabolism in the right parahippocampal gyrus and thalamus (uncorrected p < 0.001 at voxel level). Specific area(s) of hypometabolism characterised patients with persistent anosmia/ageusia, fatigue, and vascular uptake (uncorrected p < 0.005 at voxel level). CONCLUSION: [18F]FDG PET/CT acknowledged the multi-organ nature of long COVID, supporting the hypothesis of underlying systemic inflammation. Whole-body images showed increased [18F]FDG uptake in several "target" and "non-target" tissues. We found a typical pattern of brain hypometabolism associated with persistent complaints at the PET time, suggesting a different temporal sequence for brain and whole-body inflammatory changes. This evidence underlined the potential value of whole-body [18F]FDG PET in disclosing the pathophysiology of long COVID.

Vasculitis changes in COVID-19 survivors with persistent symptoms: an [18F]FDG-PET/CT study.

PURPOSE: Several patients experience unexplained persistent symptoms after SARS-CoV-2 recovering. We aimed at evaluating if 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was able to demonstrate a persistent inflammatory process. METHODS: Recovered adult COVID-19 patients, who complained unexplained persisting symptoms for more than 30 days during the follow-up visits, were invited to participate in the study. Patients fulfilling inclusion criteria were imaged by [18F]FDG positron emission tomography/computed tomography ([18F]FDG-PET/CT). Whole-body [18F]FDG-PET/CT, performed according to good clinical practice, was qualitatively (comparison with background/liver) and semi-quantitatively (target-to-blood pool ratio calculated as average SUVmax artery/average SUVmean inferior vena cava) analyzed. Negative follow-up [18F]FDG-PET/CT images of oncologic patients matched for age/sex served as controls. Mann-Whitney test was used to test differences between groups. SPSS version 26 was used for analyses. RESULTS: Ten recovered SARS-CoV-2 patients (seven male and three females, median age 52 years, range 46-80) with persisting symptoms were enrolled in the study. Common findings at visual analysis were increased [18F]FDG uptake in bone marrow and blood vessels (8/10 and 6/10 cases, respectively). [18F]FDG uptake in bone marrow did not differ between cases and controls (p = 0.16). The total vascular score was similar in the two groups (p = 0.95). The target-to-blood pool ratio resulted higher in recovered SARS-CoV-2 patients than in controls. CONCLUSION: Although the total vascular score was similar in the two groups, the target-to-blood pool ratio was significantly higher in three vascular regions (thoracic aorta, right iliac artery, and femoral arteries) in the recovered COVID-19 cohort than in controls, suggesting that SARS-CoV-2 induces vascular inflammation, which may be responsible for persisting symptoms.