Personalised PET imaging in oncology: an umbrella review of meta-analyses to guide the appropriate radiopharmaceutical choice and indication.

PURPOSE: For several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies. METHODS: We performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [18F]FDG, somatostatin- receptor-targeting 68Ga-DOTA-peptides, 18F-labelled dihydroxyphenylalanine ([18F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours. RESULTS: The literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [18F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [68Ga]Ga- DOTA-TOC and -TATE) or [18F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers. CONCLUSION: The comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations.

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.

Match Point: Nuclear Medicine Imaging for Recurrent Thyroid Cancer in TENIS Syndrome-Systematic Review and Meta-Analysis.

Background/Objectives: Disease recurrence and resistance to radioiodine (RAI) therapy are major challenges in the management of differentiated thyroid cancer (DTC). In particular, the TENIS (Thyroglobulin Elevated Negative Iodine Scintigraphy) syndrome, characterised by elevated thyroglobulin (Tg) serum levels in addition to a negative radioiodine whole body scan (WBS), complicates disease monitoring and treatment decisions. Conventional imaging techniques often fail to detect disease in WBS-negative patients with rising Tg levels, leading to limitations in therapeutic intervention. This systematic review and meta-analysis aims to evaluate the diagnostic accuracy of nuclear imaging modalities in detecting disease recurrence in patients with the TENIS syndrome and to provide insights to guide therapeutic approaches in this complex clinical scenario. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE databases up to March 2024 was performed according to PRISMA guidelines. Eligible studies were selected, and quality assessment was performed with the QUADAS-2 tool. For each study, relevant data were extracted and synthesised. A meta-analysis of the diagnostic accuracy of [18F]FDG PET/CT was performed, and patient-based pooled sensitivity and specificity were calculated using a random-effects model. Statistical heterogeneity between studies was assessed using the I2 statistic. Results: Of the 538 studies initially identified, 22 were included in the systematic review, of which 18 were eligible for meta-analysis. The eligible studies, mainly focused on [18F]FDG PET/CT, showed variable sensitivity and specificity for the detection of RAI-refractory thyroid cancer lesions. For [18F]FDG PET/CT, pooled estimates displayed a sensitivity of 0.87 (95% CI: 0.82-0.90) and a specificity of 0.76 (95% CI: 0.61-0.86), with moderate heterogeneity between studies. Conclusions: [18F]FDG PET/CT remains central in the detection of disease recurrence in patients with the TENIS syndrome. The emergence of novel radiopharmaceuticals with specific molecular targets is a promising way to overcome the limitations of [18F]FDG in these patients and to open new theranostics perspectives. This review highlights the great potential of nuclear medicine in guiding therapeutic strategies for RAI-refractory thyroid cancer.

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.

Predictors of PSMA PET Positivity: Analysis in a Selected Cohort of Biochemical Recurrence Prostate Cancer Patients after Radical Prostatectomy.

Localized prostate cancer (PCa) can be treated with radical prostatectomy (RP). Up to 30% of patients undergoing this procedure experience biochemical recurrence (BCR), namely the rise in serum prostate-specific antigen (PSA) levels during the post-surgical follow-up, requiring further treatments and with the risk of severe disease progression. Currently, the most accurate imaging technique to confirm, detect, and locate disease relapses in BCR patients is prostate-specific membrane antigen (PSMA)-targeted PET, as recommended by international clinical guidelines. The aim of the study was to investigate potential clinical and pathological predictors of PSMA PET positivity, validated by clinical and instrumental follow-up or histopathological data. In this study, a selected cohort of BCR patients after RP and no other PCa-related therapy who underwent either PSMA PET/CT or PSMA PET/MRI has been analysed. Among the considered predictors, both pathological staging after RP equal or higher than pT3a and higher PSA levels at the time of the scan were significantly correlated with PSMA PET positivity on multivariate logistic regression analysis. As expected, PSMA PET confirmed its role as an accurate imaging technique in the setting of BCR in PCa. These findings may inform appropriate and tailored patient selection and scan timing to optimize and fully exploit this powerful diagnostic tool.

Radioisotope-Guided Excision of Mediastinal Lymph Nodes in Patients with Non-Small Cell Lung Carcinoma: Feasibility and Clinical Impact.

BACKGROUND: Intraoperative localisation of nodal disease in non-small cell lung cancer (NSCLC) can be challenging. Lymph node localisation via radiopharmaceuticals is used in many conditions; we tested the feasibility of this approach in NSCLC. METHODS: NSCLC patients were prospectively recruited. Intraoperative peri-tumoral injections of [99mTc]Tc-albumin nanocolloids were performed, followed by removing the tumour and locoregional lymph nodes. These were examined ex vivo with a gamma probe and labelled sentinel lymph nodes (SLNs) if they showed any activity or non-sentinel lymph nodes (nSLNs) if they did not. Thereafter, the surgical field was scanned with the probe; any further radioactive lymph node was removed and labelled as "extra" SLNs (eSLNs). All specimens were sent to histology, and metastatic status was recorded. RESULTS: 48 patients were enrolled, and 290 nodal stations were identified: 179 SLNs, 87 nSLNs, and 24 eSLNs. A total of 44 nodal metastases were identified in 22 patients, with 36 of them (82%) located within SLNs. Patients with nSLNs metastases had at least a co-existing positive SLN. No metastases were found in eSLNs. CONCLUSIONS: The technique shows high sensitivity for intraoperative nodal metastases identification. This information could allow selective lymphadenectomies in low-risk patients or more aggressive approaches in high-risk patients.

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.

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.

ALBI grade for outcome prediction in patients affected by hepatocellular carcinoma treated with transarterial radioembolization.

Introduction and aim: Diagnosis of hepatocellular carcinoma (HCC) often occurs when the disease is unresectable and therapeutic options are limited. The extent of disease and liver function according to Child-Pugh (C-P) classification are the main prognostic factors guiding clinicians in the management of HCC. The integration of albumin-bilirubin (ALBI) grade is emerging to assess liver function on account of its objectivity and reproducibility. Our aim was to investigate the value of the ALBI grade in predicting the outcome in patients treated with transarterial radioembolization (TARE). Methods: We retrospectively enrolled patients with advanced and unresectable HCC treated with TARE in our institution. All patients underwent a preliminary dosimetric study before Yttrium-90 resin microsphere TARE. Barcelona Clinic Liver Cancer (BCLC), C-P, and ALBI scores were established at the time of TARE. Overall survival (OS), progression-free survival (PFS), and survival after TARE were assessed with the Kaplan-Meier method. Survival analyses were stratified according to ALBI grade, C-P, and BCLC classification. Univariate and multivariate Cox proportional regression models determined the association between prognostic factors and clinical outcomes. Results: In total, 72 patients were included in the study, showing an OS of 51 months. The ALBI grade identified groups of patients with different prognoses both in the whole cohort and within the C-P classes, especially between ALBI 1 and ALBI 2. This result is confirmed also within BCLC classes. In treatment naïve patients, the ALBI grade was not able to predict outcomes, whereas the presence and degree of portal vein thrombosis (PVT) significantly affected prognosis. Conclusions: The ALBI grade provided a more accurate prognostic stratification than the C-P classification in patients with intermediate and advanced HCC treated with TARE. However, the outcome of HCC is affected not only by liver function but also by disease-related characteristics, such as disease burden and degree of PVT. Including the ALBI grade in clinical guidelines may improve the management of patients affected by HCC.