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.

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.

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.

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.

[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.

[18F]Fluciclovine PET/CT: joint EANM and SNMMI procedure guideline for prostate cancer imaging-version 1.0.

The aim of this guideline is to provide standards for the recommendation, performance, interpretation, and reporting of [18F]Fluciclovine PET/CT for prostate cancer imaging. These recommendations will help to improve accuracy, precision, and repeatability of [18F]Fluciclovine PET/CT for prostate cancer essentially needed for implementation of this modality in science and routine clinical practice.

Role of 18F-FLT PET/CT in suspected recurrent or residual lymphoma: final results of a pilot prospective trial.

PURPOSE: To evaluate the role of F-18-Fluorothymidine (FLT) PET/CT in lymphoma patients with suspected recurrent or residual disease. METHODS: Adult lymphoma patients presenting with positive or equivocal F-18-FDG PET/CT at end-treatment or follow-up were prospectively addressed to an additional F-18-FLT-PET/CT. SUV max and tumour-to-background ratios (TBRs) were recorded for the most avid lesion. Biopsy or, when not available, clinical or imaging assessment were employed as standard of reference. RESULTS: Overall 52 patients were recruited. Histology was available in 20/52 patients (38%), proliferation-index (Ki-67) in 14/20. Disease was excluded in 13/52 patients (25%) (one reactive follicular hyperplasia, five reactive-inflammatory tissues, four reactive nodes, two nodal sarcoid-like and one non-specific peri-caecal finding). FDG and FLT scans were concordant in disease restaging in 34/52 patients (65%), whereas in 18/52 cases (35%) relevant discrepancies were recorded. SUV max and TBR were significantly higher in the disease versus the disease-free group, with both tracers (p = 0.0231 and 0.0219 for FDG; p = 0.0008 and 0.0016 for FLT). FLT-SUVmax demonstrated slightly better performance in discriminating benign from malignant lesions (ROC-AUC: 0.8116 and 0.7949 for FLT-SUV max and TBR; 0.7120 and 0.7140 for FDG). Optimal FLT-SUV max cut-offs were searched: three would lead to 95% sensitivity, 81% accuracy, and 39% specificity, whereas seven led to 100%, 41%, and 56% respectively. No statistically significant correlation was observed between the two FLT indices and Ki-67. CONCLUSIONS: According to our results in a clinical setting of recurrent or residual lymphoma, FLT is not significantly superior to FDG and it is unlikely that it will be employed independently. FLT may be restricted to a few specific cases, as complementary to standard FDG imaging, to confirm a diagnosis or to define a better target to biopsy. However, due to FLT suboptimal performance, many findings would remain inconclusive, requiring further diagnostic procedures and reducing the effectiveness of performing an additional FLT scan.

A review discussing fluciclovine (18F) PET/CT imaging in the detection of recurrent prostate cancer.

A significant number of patients radically treated for prostate cancer (PCa) will develop prostate-specific antigen recurrence (27-53%). Localizing the anatomical site of relapse is critical, in order to achieve the optimal treatment management. To date the diagnostic accuracy of standard imaging is low. Several desirable features have been identified for the amino-acid-based PET agent, fluciclovine (18F) including: long 18F half-life which allows more practical use in centers without a cyclotron onsite; acting as a substrate for amino acid transporters upregulated in PCa or associated with malignant phenotype; lacking of incorporation into protein; and limited urinary excretion. Fluciclovine (18F) is currently approved both in USA and Europe with specific indication in adult men with suspected recurrent PCa based on elevated prostate-specific antigen following prior treatment.

Multisite Experience of the Safety, Detection Rate and Diagnostic Performance of Fluciclovine (18F) Positron Emission Tomography/Computerized Tomography Imaging in the Staging of Biochemically Recurrent Prostate Cancer.

PURPOSE: Sensitive detection of cancer foci in men experiencing biochemical recurrence following initial treatment of prostate cancer is of great clinical significance with a possible impact on subsequent treatment choice. We describe a multisite experience of the efficacy and safety of the positron emission tomography/computerized tomography agent fluciclovine (18F) after biochemical recurrence. MATERIALS AND METHODS: A total of 596 patients underwent fluciclovine (18F) positron emission tomography/computerized tomography at 4 clinical sites. Detection rate determinations were stratified by the baseline prostate specific antigen value. Diagnostic performance was assessed against a histological reference standard in 143 scans. RESULTS: The subject level fluciclovine (18F) positron emission tomography/computer tomography detection rate was 67.7% (403 of 595 scans). Positive findings were detected in the prostate/bed and pelvic lymph node regions in 38.7% (232 of 599) and 32.6% of scans (194 of 596), respectively. Metastatic involvement outside the pelvis was detected in 26.2% of scans (155 of 591). The subject level detection rate in patients in the lowest quartile for baseline prostate specific antigen (0.79 ng/ml or less) was 41.4% (53 of 128). Of these patients 13 had involvement in the prostate/bed only, 16 had pelvic lymph node involvement without distant disease and 24 had distant metastases. The positive predictive value of fluciclovine (18F) positron emission tomography/computerized tomography scanning for all sampled lesions was 62.2%, and it was 92.3% and 71.8% for extraprostatic and prostate/bed involvement, respectively. Fluciclovine (18F) was well tolerated and the safety profile was not altered following repeat administration. CONCLUSIONS: Fluciclovine (18F) is well tolerated and able to detect local and distant prostate cancer recurrence across a wide range of prostate specific antigen values.

(18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial.

PURPOSE: To compare the accuracy of (18)F-FACBC and (11)C-choline PET/CT in patients radically treated for prostate cancer presenting with biochemical relapse. METHODS: This prospective study enrolled 100 consecutive patients radically treated for prostate cancer and presenting with rising PSA. Of these 100 patients, 89 were included in the analysis. All had biochemical relapse after radical prostatectomy (at least 3 months previously), had (11)C-choline and (18)F-FACBC PET/CT performed within 1 week and were off hormonal therapy at the time of the scans. The two tracers were compared directly in terms of overall positivity/negativity on both a per-patient basis and a per-site basis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for both the tracers; follow-up at 1 year (including correlative imaging, PSA trend and pathology when available) was considered as the standard of reference. RESULTS: In 51 patients the results were negative and in 25 patients positive with both the tracers, in eight patients the results were positive with (18)F-FACBC but negative with (11)C-choline, and in five patients the results were positive with (11)C-choline but negative with (18)F-FACBC. Overall in 49 patients the results were false-negative (FN), in two true-negative, in 24 true-positive (TP) and in none false-positive (FP) with both tracers. In terms of discordances between the tracers: (1) in one patient, the result was FN with (11)C-choline but FP with (18)F-FACBC (lymph node), (2) in seven, FN with (11)C-choline but TP with (18)F-FACBC (lymph node in five, bone in one, local relapse in one), (3) in one, FP with (11)C-choline (lymph node) but TP with (18)F-FACBC (local relapse), (4) in two, FP with (11)C-choline (lymph nodes in one, local relapse in one) but FN with (18)F-FACBC, and (5) in three, TP with (11)C-choline (lymph nodes in two, bone in one) but FN with (18)F-FACBC. With (11)C-choline and (18)F-FACBC, sensitivities were 32 % and 37 %, specificities 40 % and 67 %, accuracies 32 % and 38 %, PPVs 90 % and 97 %, and NPVs 3 % and 4 %, respectively. Categorizing patients by PSA level (<1 ng/ml 28 patients, 1 - <2 ng/ml 28 patients, 2 - <3 ng/ml 11 patients, ≥3 ng/ml 22 patients), the number (percent) of patients with TP findings were generally higher with (18)F-FACBC than with (11)C-choline: six patients (21 %) and four patients (14 %), eight patients (29 %) and eight patients (29 %), five patients (45 %) and four patients (36 %), and 13 patients (59 %) and 11 patients (50 %), respectively. CONCLUSION: (18)F-FACBC can be considered an alternative tracer superior to (11)C-choline in the setting of patients with biochemical relapse after radical prostatectomy.

Nuclear medicine in urological cancers: what is new?

The diffusion of PET/computed tomography has opened up a new role for nuclear imaging in urological oncology. Prostate cancer is evaluated with choline ((11)C or (18)F) PET due to a lack of sensitivity of (18)F-fluorodeoxyglucose (FDG). However, many new tracers, such as (18)F-fluorocyclobutane-1-carboxylic acid and (68)Ga-prostate-specific membrane antigen, are under investigation, offering promising results in the particular setting of radically treated patients with biochemical relapse. The performance of (18)F-FDG depends on the histological type; indeed, renal cell cancer may present variable metabolic uptake. In this field, mainly antibodies labeled with positron emitters are under clinical evaluation. Finally, (18)F-FDG PET/computed tomography has been proven to show good accuracy in detecting metastatic testicular and bladder cancers, despite not having valid results in detecting local disease. The urological cancer diagnostic process is currently under continuous development.

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.

ß1600 Q.Clear Digital Reconstruction of [68Ga]Ga-DOTANOC PET/CT Improves Image Quality in NET Patients.

Background: Image reconstruction is crucial for improving overall image quality and diagnostic accuracy. Q.Clear is a novel reconstruction algorithm that reduces image noise. The aim of the present study is to assess the preferred Q.Clear ß-level for digital [68Ga]Ga-DOTANOC PET/CT reconstruction vs. standard reconstruction (STD) for both overall scan and single-lesion visualization. Methods: Inclusion criteria: (1) patients with/suspected neuroendocrine tumors included in a prospective observational monocentric study between September 2019 and January 2022; (2) [68Ga]Ga-DOTANOC digital PET/CT and contrast-enhanced-CT (ceCT) performed at our center at the same time. Images were reconstructed with STD and with Q.Clear ß-levels 800, 1000, and 1600. Scans were blindly reviewed by three nuclear-medicine experts: the preferred ß-level reconstruction was independently chosen for the visual quality of both the overall scan and the most avid target lesion < 1 cm (t) and >1 cm (T). PET/CT results were compared to ceCT. Semiquantitative analysis was performed (STD vs. ß1600) in T and t concordant at both PET/CT and ceCT. Subgroup analysis was also performed in patients presenting discordant t. Results: Overall, 52 patients were included. ß1600 reconstruction was considered superior over the others for both overall scan quality and single-lesion detection in all cases. The only significantly different (p < 0.001) parameters between ß1600 and STD were signal-to-noise liver ratio and standard deviation of the liver background. Lesion-dependent parameters were not significantly different in concordant T (n = 37) and t (n = 10). Among 26 discordant t, when PET was positive, all findings were confirmed as malignant. Conclusions: ß1600 Q.Clear reconstruction for [68Ga]Ga-DOTANOC imaging is feasible and improves image quality for both overall and small-lesion assessment.

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.

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.

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.

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.

FDG PET/CT predictive role in follicular lymphoma.

PURPOSE: We present findings concerning (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) at end-treatment evaluation in follicular lymphoma (FL) in order to establish possible predictive factors for progression-free survival (PFS) and patient outcome. METHODS: We retrospectively analysed data from 91 consecutive FL patients (M:F = 51:40, mean age 61) referred to our PET Unit at therapy completion: 38 with an indolent form (grade 1-2) and 53 with an aggressive FL (grade 3a and b) according to the World Health Organization (WHO) classification. A total of 148 FDG PET/CT scans were analysed and findings reported as positive or negative for disease. The overall response to treatment was assessed according to the revised International Workshop Criteria (IWC). The final outcome was defined as remission or disease by taking clinical, instrumental and histological data as standards of reference, with a mean follow-up period of 3 years (range 1-8). A statistical analysis was performed with respect to PFS and patient outcome for FDG PET result, tumour grading, Follicular Lymphoma International Prognostic Index (FLIPI), disease stage and number of relapses, on uni- and multivariate analyses, with p < 0.05 considered as significant. RESULTS: Overall patients presented a mean PFS of 35 months (range 3-86), with a relapse rate of 42%. At final outcome, remission was achieved in 67 of 91 patients (74%). Of the different predictive factors, only FDG PET result significantly correlated with patient outcome (p = 0.0002). PET/CT performance at the end of treatment was as follows: 100% sensitivity, 99% specificity, 89% positive predictive value and 100% negative predictive value. The Kaplan-Meier analysis demonstrated a statistically significant correlation with PFS for FDG PET (p < 0.0001), FLIPI score (0-1 versus ≥ 2) (p = 0.0451) and number of relapses (none versus ≥ 1) (p = 0.0058). These findings were confirmed at the univariate analysis, whereas at the multivariate analysis only FDG PET (p = 0.0006892) and number of relapses (p = 0.01947) were independent predictive factors for PFS. CONCLUSION: End-treatment PET/CT in FL has high accuracy and appears to be a good predictor of PFS and patient outcome, irrespective of grading. As expected, patients facing more than one relapse seem to have significantly shorter PFS in the presence of a positive FDG PET.

Early interim 18F-FDG PET in Hodgkin's lymphoma: evaluation on 304 patients.

PURPOSE: The use of early (interim) PET restaging during first-line therapy of Hodgkin's lymphoma (HL) in clinical practice has considerably increased because of its ability to provide early recognition of treatment failure allowing patients to be transferred to more intensive treatment regimens. METHODS: Between June 1997 and June 2009, 304 patients with newly diagnosed HL (147 early stage and 157 advanced stage) were treated with the ABVD regimen at two Italian institutions. Patients underwent PET staging and restaging at baseline, after two cycles of therapy and at the end of the treatment. RESULTS: Of the 304 patients, 53 showed a positive interim PET scan and of these only 13 (24.5%) achieved continuous complete remission (CCR), whereas 251 patients showed a negative PET scan and of these 231 (92%) achieved CCR. Comparison between interim PET-positive and interim PET-negative patients indicated a significant association between PET findings and 9-year progression-free survival and 9-year overall survival, with a median follow-up of 31 months. Among the early-stage patients, 19 had a positive interim PET scan and only 4 (21%) achieved CCR; among the 128 patients with a negative interim PET scan, 122 (97.6%) achieved CCR. Among the advanced-stage patients, 34 showed a persistently positive PET scan with only 9 (26.4%) achieving CCR, whereas 123 showed a negative interim PET scan with 109 (88.6%) achieving CCR. CONCLUSION: Our results demonstrate the role of an early PET scan as a significant step forward in the management of patients with early-stage or advanced-stage HL.