Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update.

PURPOSE OF REVIEW: This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT). RECENT FINDINGS: Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.

Real-Life Use of [68Ga]Ga-DOTANOC PET/CT in Confirmed and Suspected NETs from a Prospective 5-Year Electronic Archive at an ENETS Center of Excellence: More Than 2000 Scans in More Than 1500 Patients.

The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting.

Actionable imaging findings in the daily PET/CT scenario.

Background and aim: The American College of Radiology (ACR) defines "actionable findings" the ones requiring a special communication between radiologists and referring clinicians, suggesting to organize their categorization in a three-degree scale on the basis of the risk for the patient to develop complications. These cases may fall in a grey-zone communication between different care figures with the risk of being underestimated or even not being considered at all. In this paper, our aim is to adapt the ACR categorization to the most frequent actionable findings encountered when reporting PET/CT images in a Nuclear Medicine Department, describing the most frequent and relevant imaging features and presenting the modalities of communication and the related clinical interventions that can be modulated by the prognostic severity of the clinical cases. Materials and methods: We performed a descriptive, observational and critical analysis of the most relevant literature on the topic of "actionable findings", in particular, starting from the reports of the ACR Actionable Reporting Work Group, we categorised and described, in a narrative review, the most relevant "actionable findings" encountered in the Nuclear Medicine PET/CT daily practice. Results: To the best of our knowledge, to date there are no clear indications on this selective PET/CT topic, considering that the current recommendations target mainly radiologists and assume a certain level of radiological expertise. We resumed and classified the main imaging conditions under the term of "actionable findings" according to the corresponding anatomical districts, and we described their most relevant imaging features (independently of PET avidity or not). Furthermore, a different communication timing and strategy was suggested on the basis of the findings' urgency. Conclusion: A systematic categorization of the actionable imaging findings according to their prognostic severity may help the reporting physician to choose how and when to communicate with the referring clinician or to identify cases requiring a prompt clinical evaluation. Effective communication is a critical component of diagnostic imaging: timely receipt of the information is more important than the method of delivery.

Case report: PSMA PET/CT addresses the correct diagnosis in a patient with metastatic prostate cancer despite negative core biopsies and mpMRI. A diagnostic challenge.

This is a case of [68 Ga]Ga-Prostate-specific membrane antigen (PSMA)-11 PET/CT in a 73-years old patient presenting high Prostate Specific Antigen (PSA) levels despite both multi-parametric magnetic resonance imaging (mpMRI) and 12-core saturation biopsy negative for prostate cancer (Pca). This is a highly interesting case because, despite the advanced metastatic spread at initial presentation as showed by [68Ga]Ga-PSMA-PET/CT, the primary Pca was detected by none of the diagnostic techniques (12 random sample biopsy, mpMRI, PSMA PET/CT). However, [68Ga]Ga-PSMA-PET/CT showed a suspicious axillary lesion suitable for biopsy, which finally resulted as Pca metastasis. This case report is therefore a brilliant example of how [68Ga]Ga-PSMA-PET/CT optimized patient's management.

Hepatobiliary scintigraphy to predict postoperative liver failure after major liver resection; a multicenter cohort study in 547 patients.

BACKGROUND: This study aimed to analyze the predictive value of Hepatobiliary scintigraphy (HBS) for posthepatectomy liver failure (PHLF) after major liver resection with a comparison to assessment of liver volume in a multicenter cohort. METHODS: Patients who underwent liver resection after HBS were included from six centers. Remnant liver volume was calculated from CT images. PHLF was scored and graded according to the grade B/C ISGLS criteria. RESULTS: In 547 patients PHLF incidence was 10% (56/547) and 90-day mortality rate 8% (42/547). Overall predictive value of remnant liver function was 0.66 (0.58-0.74) and similar to that of remnant volume (0.63 (0.72). For biliary tumors, a function cut-off of 2.7%/min/m2 and 30% volume cut-off resulted in a PHLF rate 12% and 13%, respectively. While an 8.5%/min (4.5%/min/m2) function cut-off resulted in 7% PHLF for those with a function above the cutoff while a 40% volume cutoff still resulted in 14% PHLF rate. In the multivariable analyses for PHLF, liver function was predictive but liver volume was not. CONCLUSION: The current study shows that preoperative liver function assessment using HBS is at least as predictive for PHLF as liver volume assessment, and likely has several advantages, particularly in the high-risk sub-group of biliary tumors.

Molecular imaging Theranostics of Neuroendocrine Tumors.

Neuroendocrine neoplasms (NEN) are rare and heterogeneous tumors, originating mostly from the gastro-entero-pancreatic (GEP) tract followed by the lungs. Multidisciplinary discussion is mandatory for optimal diagnostic and therapeutic management. Well-differentiated NEN (NET) present a high expression of somatostatin receptors (SSTR) and can be studied with [68Ga]-DOTA-peptides ([68Ga]Ga-DOTANOC, [68Ga]Ga-DOTATOC, [68Ga]Ga-DOTATATE) PET/CT to assess disease extension and the eligibility for peptide receptor radionuclide therapy (PRRT). SSTR-analogues labelled with 90Y or 177Lu have been used since mid-90s for NET therapy. PRRT is now considered an effective and safe treatment option for SSTR-expressing NET: following the approval of 177Lu-DOTATATE by FDA and EMA, PRRT is now part of the therapeutic algorithms of the main scientific societies. New strategies to improve PRRT efficacy and to reduce its toxicity are under evaluation (eg, personalization of treatment schemes, the selection of the most suitable patients, improvement of response assessment criteria, optimization of treatment sequencing, feasibility of PRRT-retreatment, combination of PRRT with other treatments options). Recently, several emerging radiopharmaceuticals showed encouraging results for both imaging and therapy (eg, SSTR-analogues labelled with 18F, SSTR-antagonists for both diagnosis and therapy, alpha-labelling for therapy, radiopharmaceuticals binding to new cellular targets). Aim of this review is to focus on current knowledge and to outline emerging perspectives for NEN's diagnosis and therapy.

PET/CT in Non-Hodgkin Lymphoma: An Update.

Non-Hodgkin lymphomas represents a heterogeneous group of lymphoproliferative disorders characterized by different clinical courses, varying from indolent to highly aggressive. 18F-FDG-PET/CT is the current state-of-the-art diagnostic imaging, for the staging, restaging and evaluation of response to treatment in lymphomas with avidity for 18F-FDG, despite it is not routinely recommended for surveillance. PET-based response criteria (using five-point Deauville Score) are nowadays uniformly applied in FDG-avid lymphomas. In this review, a comprehensive overview of the role of 18F-FDG-PET in Non-Hodgkin lymphomas is provided, at each relevant point of patient management, particularly focusing on recent advances on diffuse large B-cell lymphoma and follicular lymphoma, with brief updates also on other histotypes (such as marginal zone, mantle cell, primary mediastinal- B cell lymphoma and T cell lymphoma). PET-derived semiquantitative factors useful for patient stratification and prognostication and emerging radiomics research are also presented.

[68Ga]Ga-DOTANOC Uptake at Pancreatic Head/Uncinate Process: Is It a Persistent Diagnostic Pitfall Over Time?

PURPOSE: [68Ga]Ga-DOTA-peptide uptake in the pancreatic head/uncinate process (UP) is a frequent PET/CT finding. Although mostly physiologic, it can represent a pitfall in PET/CT reading, especially when focal. An increased frequency of UP uptake has been reported in patients (pts) affected by diabetes mellitus (DM). The aim of the study is to describe the frequency of [68Ga]Ga-DOTANOC UP uptake to evaluate its variations over time and its possible correlation with DM. METHODS: In September 2017, a monocentric prospective observational electronic archive was initiated at our center to collect clinical and imaging data of pts undergoing [68Ga]Ga-DOTANOC PET/CT. Among the pts enrolled in the first 6 months (Sept 2017 to Feb 2018), those presenting [68Ga]Ga-DOTANOC PET/CT uptake at UP level were included. Pts with UP lesions already documented on CT/MRI or those that underwent surgical excision of UP before PET/CT were excluded from the analysis. [68Ga]Ga-DOTANOC UP uptake was classified as diffuse or focal and compared with the pattern observed in previous PET/CT scans performed at our center. An increased frequency of UP uptake was also correlated with the presence of DM. RESULTS: In the first 6 months, 253 pts were enrolled in the archive and 172 out of them were included in the analysis. UP increased uptake was frequently observed (77/172, 44.8%) and was mostly diffuse (62/77). In 75/172 pts (43.6%), previous [68Ga]Ga-DOTANOC PET/CT scans were available (overall 268 scans; number of previous PET per pt range: 1-20) and were retrospectively reviewed. Despite the fact that, in most pts, the uptake pattern was stable over time (54/75 pts, 72%), it changed in approximately one third of cases (21/75, 28%). Among DM pts (29/172), only 10/29 (34.4%) presented increased UP uptake. CONCLUSIONS: UP [68Ga]Ga-DOTANOC uptake is a frequent non-malignant finding (slightly higher than previously reported), mostly presenting with a diffuse pattern. However, contrary to previous reports, our data show that the pattern of uptake may vary over time in approximately one third of the cases and it is not more frequently observed in pts with DM.

Two birds with one stone: can [68Ga]Ga-DOTANOC PET/CT image quality be improved through BMI-adjusted injected activity without increasing acquisition times?

OBJECTIVES: To assess how patients' dependent parameters may affect [68Ga]Ga-DOTANOC image quality and to propose a theoretical body mass index (BMI)-adjusted injected activity (IA) scheme, to improve imaging of high weight patients. METHODS: Among patients prospectively enrolled (June-2019 and May-2020) in an Institutional Ethical Committee-approved electronic archive, we included those affected by primary gastro-entero-pancreatic (GEP) or lung neuroendocrine tumour and referred by our Institutional clinicians (excluding even minimal radiopharmaceutical extravasation, movement artefacts, renal insufficiency). All PET/CT images were acquired following EANM guidelines and rated for visual quality (1 = non-diagnostic, 2 = poor, 3 = moderate, 4 = good). Collected data included patient's body mass, height, BMI, age, IA (injected activity), IA/Kg (IAkg), IA/BMI (IABMI), liver SUVmean, liver SUVmax standard deviation, liver-signal-to-noise (LSNR), normalised_LSNR (LSNR_norm) and contrast-to-noise ratio (CNR) for positive scans and were compared to image rating (poor vs moderate/good). RESULTS: Overall, 77 patients were included. Rating concordance was high (agreement = 81.8%, Fleiss k score = 0.806). All patients' dependent parameters resulted significantly different between poor-rated and moderate/good-rated scans (IA: p = 0.006, IAkg: p =< 0.001, body weight: p =< 0.001, BMI: p =< 0.001, IABMI: p =< 0.001). Factors significantly associated with moderate/good rating were BMI (p =< 0.001), body weight (p =< 0.001), IABMI (p =< 0.001), IAkg (p = 0.001), IA (p = 0.003), LSNR_norm (p = 0.01). The BMI-based model presented the best predictive efficiency (81.82%). IABMI performance to differentiate moderate/good from poor rating resulted statistically significant (IA-AUC = 0.78; 95% CI: 0.68-0.89; cut-off value of 4.17 MBq*m2/kg, sensitivity = 81.1%, specificity = 66.7%). If BMI-adjusted IA (=4.17*BMI) would have been applied in this population, the median IA would have slightly inferior (-4.8%), despite a different IA in each patient. ADVANCES IN KNOWLEDGE: BMI resulted the best predictor of image quality. The proposed theoretical BMI-adjusted IA scheme (4.17*BMI) should yield images of better quality (especially in high-BMI patients) maintaining practical scanning times (3 min/bed).

New PET Radiotracers for the Imaging of Neuroendocrine Neoplasms.

OPINION STATEMENT: Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumours derived from cells of neuroendocrine origin and can potentially arise everywhere in the human body. The diagnostic assessment of NEN can be performed using a variety of PET radiopharmaceuticals. Well-differentiated NEN (NET) present a high expression of SSTR (somatostatin receptors) and can therefore be studied with 68Ga-DOTA-peptides ([68Ga]Ga-DOTANOC, [68Ga]Ga-DOTATOC, [68Ga]Ga-DOTATATE). Current guidelines recommend the use of SSTR imaging to assess disease extension at staging/restaging, follow-up, assessment of response to therapy and selection of patients who may benefit from radionuclide therapy (PRRT). [18F]F-FDG is used for the assessment of high-grade tumours (high-grade G2, G3 and NEC) and in every case, there is one or more mismatched lesions between diagnostic CT (positive) and SSTR-PET/CT (negative). [18F]F-DOPA is currently used for the assessment of medullary thyroid carcinoma, neuroblastoma, primary pheochromocytoma and abdominal paraganglioma. In recent years, however, several new tracers were designed exploiting the many potential targets of the neuroendocrine cell and were employed in clinical trials for both imaging and therapy. Currently, the real-life clinical impact of these tracers is still mostly not known; however, the favourable biodistribution (e.g. [68Ga]Ga-FAPI, SSTR antagonists) and the possibility to use new theranostic pairs may provide novel diagnostic as well as therapeutic options (e.g. [68Ga]Ga-PSMA, [64Cu]Cu-SARTATE, [68Ga]Ga-CXCR4) for NEN patients.

A Peculiar 18 F-FDG Spinal Uptake Helps Diagnosis and Effective Treatment of Polymyalgia Rheumatica : "The Corset Sign".

ABSTRACT: Polymyalgia rheumatica is the most common inflammatory rheumatic disease in elderly people, usually develops in patients older than 50 years, more frequently in females. An emerging imaging tool in the diagnostic workup of this condition is whole-body PET/CT, which allows an overall assessment of the articular and extra-articular structures involved.

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors.

Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors that require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for diagnosis and with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and as a criteria for peptide receptor radionuclide therapy (PRRT) eligibility based on somatostatin receptor (SSTR) expression. On the diagnostic side, [68Ga]Ga-DOTA peptides PET/CT (SSTR PET/CT) is the gold standard for imaging well-differentiated SSTR-expressing neuroendocrine tumors (NETs). [18F]FDG PET/CT is useful in higher grade NENs (NET G2 with Ki-67 > 10% and NET G3; NEC) for more accurate disease characterization and prognostication. Promising emerging radiopharmaceuticals include somatostatin analogues labelled with 18F (to overcome the limits imposed by 68Ga), and SSTR antagonists (for both diagnosis and therapy). On the therapeutic side, the evidence gathered over the past two decades indicates that PRRT is to be considered as an effective and safe treatment option for SSTR-expressing NETs, and is currently included in the therapeutic algorithms of the main scientific societies. The positioning of PRRT in the treatment sequence, as well as treatment personalization (e.g., tailored dosimetry, re-treatment, selection criteria, and combination with other alternative treatment options), is warranted in order to improve its efficacy while reducing toxicity. Although very preliminary (being mostly hampered by lack of methodological standardization, especially regarding feature selection/extraction) and often including small patient cohorts, radiomic studies in NETs are also presented. To date, the implementation of radiomics in clinical practice is still unclear. The purpose of this review is to offer an overview of radiolabeled SSTR analogues for theranostic use in NENs.

Can Q.Clear reconstruction be used to improve [68 Ga]Ga-DOTANOC PET/CT image quality in overweight NEN patients?

AIM/INTRODUCTION: Digital PET/CT allows Q.Clear image reconstruction with different Beta (ß) levels. However, no definitive standard ß level for [68 Ga]Ga-DOTANOC PET/CT has been established yet. As patient's body mass index (BMI) can affect image quality, the aim of the study was to visually and semi-quantitatively assess different ß levels compared to standard OSEM in overweight patients. MATERIALS AND METHODS: Inclusion criteria: (1) patients with NEN included in a prospective CE-approved electronic archive; (2) [68 Ga]Ga-DOTANOC PET/CT performed on a digital tomograph between September2019/March2021; (3) BMI ≥ 25. Images were acquired following EANM guidelines and reconstructed with OSEM and Q.Clear with three ß levels (800, 1000, 1600). Scans were independently reviewed by three expert readers, unaware of clinical data, who independently chose the preferred ß level reconstruction for visual overall image quality. Semi-quantitative analysis was performed on each scan: SUVmax of the highest uptake lesion (SUVmax-T), liver background SUVmean (SUVmean-L), SUVmax-T/SUVmean-L, Signal-to-noise ratio for both liver (LSNR) and the highest uptake lesion (SNR-T), Contrast-to-noise ratio (CNR). RESULTS: Overall, 75 patients (median age: 63 years old [23-87]) were included: pre-obesity sub-group (25 ≤ BMI < 30, n = 50) and obesity sub-group (BMI ≥ 30, n = 25). PET/CT was positive for disease in 45/75 (60.0%) cases (14 obese and 31 pre-obese patients). Agreement among readers' visual rating was high (Fleiss κ = 0.88) and the ß1600 was preferred in most cases (in 96% of obese patients and in 53.3% of pre-obese cases). OSEM was considered visually equal to ß1600 in 44.7% of pre-obese cases and in 4% of obese patients. In a minority of pre-obese cases, OSEM was preferred (2%). In the whole population, CNR, SNR-T and LSNR were significantly different (p < 0.001) between OSEM and ß1600, conversely to SUVmean-L (not significant). These results were also confirmed when calculated separately for the pre-obesity and obesity sub-groups ß800 and ß1000 were always rated inferior. CONCLUSIONS: Q.Clear is a new technology for PET/CT image reconstruction that can be used to increase CNR and SNR-T, to subsequently optimise overall image quality as compared to standard OSEM. Our preliminary data on [68 Ga]Ga-DOTANOC PET/CT demonstrate that in overweight NEN patients, ß1600 is preferable over ß800 and ß1000. Further studies are warranted to validate these results in lesions of different anatomical region and size; moreover, currently employed interpretative PET positivity criteria should be adjusted to the new reconstruction method.

Impact of 18F-FDG PET/CT on Clinical Management of Suspected Radio-Iodine Refractory Differentiated Thyroid Cancer (RAI-R-DTC).

BACKGROUND: As reported in the literature, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) provides useful qualitative and semi-quantitative data for the prognosis of advanced differentiated thyroid cancer. Instead, there is a lack of data about the real clinical impact of 18F-FDG PET/CT on the choice of the more effective therapeutic approach for advanced differentiated thyroid cancer (DTC) that starts to lose iodine avidity. The primary aim of this retrospective study was to assess how 18F-FDG PET/CT can guide the choice of the best therapeutic approach to RAI-refractory DTC (RAI-R-DTC) in patients with a doubtful iodine uptake/negative 18F-FDG PET/CT I whole-body scan after several radioactive iodine therapies (RAIT). The secondary aim was to assess the prognostic role of clinical and semi-quantitative metabolic 18F-FDG PET/CT parameters in comparison to published data. MATERIALS AND METHODS: A monocentric retrospective observational study was performed, reviewing the medical records of 53 patients recruited from a database of 208 patients treated at our Institution between 2011 and 2019, with advanced DTC that underwent FDG PET/CT scan for a suspected RAI-R-DTC. Selected patients had to perform a 18F-FDG PET/CT scan after the second RAIT based on a doubtful iodine uptake/negative 131 I whole-body scan and/or persistent elevated thyroglobulin levels. Metabolic response was defined according to positron emission tomography response criteria in solid tumors (PERCIST) guidelines. Standardized uptake value (SUV)max, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The association between metabolic features, clinical parameters and progression free survival (PFS) was assessed applying Kruskal-Wallis, chi-square-Pearson correlation tests, and Cox regression analyses when appropriate. RESULTS: Among our sample of 53 patients (mean age 52.0 ± 19.9 years; 31 women and 22 men), 27 (51.0%) presented a positive 18F-FDG PET/CT scan: 16 (59.0%) underwent watchful waiting, 4 (15.0%) received external-beam radiation therapy (EBRT), 4 (15.0%) underwent surgery, 2 (7.4%) received another course of RAI therapy, and 1 underwent surgery + EBRT. PERCIST response was evaluated in 14/27 patients. Median follow-up was 5.8 ± 3.9 years and median PFS was 38.0 ± 21.8 months. At the last follow-up assessment, 14/53 (26.4%) demonstrated disease progression, 13/53 (24.5) persistence of structural disease, 25/53 (47%) persistence of biochemical disease, and 15/53 (28%) had an excellent response. A significant association was found between therapeutic approach, metabolic response, and final disease response evaluation, as well as a linear correlation between MTV and TLG with thyroglobulin level. CONCLUSIONS: Our Institutional experience confirmed the role of 18F-FDG PET/CT as a useful guide in the clinical management of RAI-R-DTC and obviated further unnecessary RAIT.

PET/CT Variants and Pitfalls in Prostate Cancer: What You Might See on PET and Should Never Forget.

2-deoxy-2-[18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) gained an impressive role in the diagnostic management of many oncological diseases, even though its use in imaging prostate cancer (PC) is limited to selected cases, mostly advanced stage of PC and selection for prostate specific antigen membrane (PSMA) radioligand therapy (RLT). In the past years, several PET tracers have been developed for both staging and restaging PC. The three most employed PET molecules in daily practice are [11C] or [18F]F-Choline, [18F]F-Fluciclovine (Anti-1- amino-3-[18F]Fluorocyclobutane-1-Carboxylic Acid, also known as (Anti-[18F]FACBC), [68Ga]Ga-PSMA and recently FDA approved the first Fluorinated PSMA-based named [18F]F-DCFPyl. Each one has its own physiological and peculiarity which are worth exploring. Moreover, an increasing number of case reports and studies have reported tracers' variants, pitfalls, or even non-prostatic diseases (benign and malignant) incidentally detected. In prostate oncology, PET can be performed with several indications in different stages of disease, as highlighted in the EAU Guidelines on PC. A correct scan interpretation depends on the knowledge of both the physiological distribution of the tracers and the uptake of possible variants and pitfalls. The aim of this critical review is to provide a comprehensive knowledge of physiological distribution of these three tracers, as well as an updated overview of variants and pitfalls.

[18F]-Fluciclovine PET/CT for preoperative nodal staging in high-risk primary prostate cancer: final results of a prospective trial.

PURPOSE: The conventional imaging flowchart for prostate cancer (PCa) staging may fail in correctly detecting lymph node metastases (LNM). Pelvic lymph node dissection (PLND) represents the only reliable method, although invasive. A new amino acid PET compound, [18F]-fluciclovine, was recently authorized in suspected PCa recurrence but not yet included in the standard staging work-up of primary PCa. A prospective monocentric study was designed to evaluate [18F]-fluciclovine PET/CT diagnostic performance for preoperative LN staging in primary high-risk PCa. METHODS: Consecutive patients (pts) with biopsy-proven PCa, standard staging (including [11C]choline PET/CT), eligible for PLND, were enrolled to undergo an investigational [18F]-fluciclovine PET/CT. Nodal uptake higher than surrounding background was reported by at least two readers (blinded to [11C]choline) using a visual 5-point scale (1-2 probably negative; 4-5 probably positive; 3 equivocal); SUVmax, target-to-background (aorta-A; bone marrow-BM) ratios (TBRs), were also calculated. PET results were validated with PLND. [18F]-fluciclovine PET/CT performance using visual score and semi-quantitative indexes was analyzed both per patient and per LN anatomical region, compared to conventional [11C]choline and clinical predictive factors (to note that diagnostic performance of [18F]-fluciclovine was explored for LNM but not examined for intrapelvic or extrapelvic M1 lesions). RESULTS: Overall, 94 pts underwent [18F]-fluciclovine PET/CT; 72/94 (77%) high-risk pts were included in the final analyses (22 pts excluded: 8 limited PLND; 3 intermediate-risk; 2 treated with radiotherapy; 4 found to be M1; 5 neoadjuvant hormonal therapy). Median LNM risk by Briganti nomogram was 19%. LNM confirmed on histology was 25% (18/72 pts). Overall, 1671 LN were retrieved; 45/1671 (3%) LNM detected. Per pt, median no. of removed LN was 22 (mean 23 ± 10; range 8-51), of LNM was 2 (mean 3 ± 2; range 1-10). Median LNM size was 5 mm (mean 5 ± 2.5; range 2-10). On patient-based analyses (n = 72), diagnostic performance for LNM resulted significant with [18F]-fluciclovine (AUC 0.66, p 0.04; 50% sensitivity, 81% specificity, 47% PPV, 83% NPV, 74% accuracy), but not with [11C]choline (AUC 0.60, p 0.2; 50%, 70%, 36%, 81%, and 65% respectively). Briganti nomogram (OR = 1.03, p = 0.04) and [18F]-fluciclovine visual score (≥ 4) (OR = 4.27, p = 0.02) resulted independent predictors of LNM at multivariable analyses. On region-based semi-quantitative analyses (n = 576), PET/CT performed better using TBR parameters (TBR-A similar to TBR-BM; TBR-A fluciclovine AUC 0.61, p 0.35, vs choline AUC 0.57 p 0.54; TBR-BM fluciclovine AUC 0.61, p 0.36, vs choline AUC 0.58, p 0.52) rather than using absolute LN SUVmax (fluciclovine AUC 0.51, p 0.91, vs choline AUC 0.51, p 0.94). However, in all cases, diagnostic performance was not statistically significant for LNM detection, although slightly in favor of the experimental tracer [18F]-fluciclovine for each parameter. On the contrary, visual interpretation significantly outperformed PET semi-quantitative parameters (choline and fluciclovine: AUC 0.65 and 0.64 respectively; p 0.03) and represents an independent predictive factor of LNM with both tracers, in particular [18F]-fluciclovine (OR = 8.70, p 0.002, vs OR = 3.98, p = 0.03). CONCLUSION: In high-risk primary PCa, [18F]-fluciclovine demonstrates some advantages compared with [11C]choline but sensitivity for metastatic LN detection is still inadequate compared to PLND. Visual (combined morphological and functional), compared to semi-quantitative assessment, is promising but relies mainly on readers' experience rather than on unquestionable LN avidity. TRIAL REGISTRATION: EudraCT number: 2014-003,165-15.

Overview and recent advances in PET/CT imaging in lymphoma and multiple myeloma.

Imaging in hematological diseases has evolved extensively over the past several decades. Positron emission tomography/computed tomography (PET/CT) with of 2-[18 F]-fluoro-2-deoxy-d-glucose ([18 F] FDG) is currently essential for accurate staging and for early and late therapy response assessment for all FDG-avid lymphoproliferative histologies. The widely adopted visual Deauville 5-point scale and Lugano Classification recommendations have recently standardized PET scans interpretation and improved lymphoma patient management. In addition [18 F] FDG-PET is routinely recommended for initial evaluation and treatment response assessment of Multiple Myeloma (MM) with significant contribution in risk-stratification and prognostication, although magnetic resonance imaging remains the Gold Standard for the assessment of bone marrow involvement. In this review, an overview of the role of [18 F] FDG-PET, in hematological malignancies is provided, particularly focusing on Hodgkin lymphoma (HL) and Diffuse Large B Cell Lymphoma (DLBCL), both in adult and pediatric populations, and MM, at each point of patient management. Potential alternative molecular imaging applications in this field, such as non-[18 F] FDG-tracers, whole body magnetic resonance imaging (WB-MRI), hybrid PET/MRI and emerging radiomics research are briefly presented.

The Role of [18F]Fluciclovine PET/CT in the Characterization of High-Risk Primary Prostate Cancer: Comparison with [11C]Choline PET/CT and Histopathological Analysis.

The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax; target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology; subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the "blinded" prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively; whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.

The role of hepatobiliary scintigraphy combined with spect/ct in predicting severity of liver failure before major hepatectomy: a single-center pilot study.

Hepatobiliary scintigraphy (HBS) has been demonstrated to predict post-hepatectomy liver failure (PHLF). However, existing cutoff values for future liver remnant function (FLR-F) were previously set according to the "50-50 criteria" PHLF definition. Methods of calculation and fields of application in liver surgery have changed in the meantime. The aim of this study was to demonstrate the role of HBS combined with single photon emission computed tomography (SPECT/CT) in predicting severity of PHLF, according to the International Study Group of Liver Surgery (ISGLS). All patients submitted to major hepatectomy with preoperative HBS-SPECT/CT between November 2016 and December 2019, were analyzed. Patients were resected according to hepatic volumetry. Receiver operating characteristic (ROC) curve analysis was performed to identify cutoffs of FLR function for predicting PHLF according to ISGLS definition and grading. Of the 38 patients enrolled, 26 were submitted to one-stage hepatectomy (living liver donors = 4) and 12 to two-stage procedures (portal vein embolization = 4, ALPPS = 8). Overall, 18 patients developed PHLF according to ISGLS criteria: 12 of grade A (no change in the patient's clinical management) and 6 of grade B (change in clinical management). ROC analysis established increasingly higher cutoffs of FLR-F for predicting PHLF according to the "50-50 criteria", ISGLS grade B and ISGLS grade A/B, respectively. HBS with SPECT/CT may help to assess severity of PHLF following major hepatectomy. Prospective multicenter trials are needed to confirm the effective role of HBS-SPECT/CT in liver surgery.