The future of choline PET in the era of prostate specific membrane antigen.

Radiolabeled choline was the first radiopharmaceutical agent employed in prostate cancer patients. It has been considered a metabolic agent able to detect the presence of prostate cancer cell, both in the initial phase of the disease and in the restaging setting. Three agents are now available in clinical practice: one radiolabeled with 11C (called 11C-Choline) and two with 18F (either as 18F-methylcholine or 18F-ethylcholine). During the years, different studies have been performed with 11C -Choline and 18F-Choline demonstrating their performance for the detection of prostate cancer, in different settings of the disease. However, recently, new radiopharmaceutical agents for prostate cancer have been developed, gaining an important role for the diagnosis of prostate cancer, particularly in the restaging setting. The present review has been conceived in order to discuss the current role of radiolabeled choline PET/CT in the era of new agents for prostate cancer, in particular in the era of radiolabeled PSMA.

Impact of patient's habitus on image quality and quantitative metrics in 18F-FDG PET/CT images.

PURPOSE: To study how the quantitative parameters of 18F-FDG PET imaging change with the emission scan duration (ESD) and the body-mass-index (BMI) in phantom and patients on a time-of-flight (TOF)-PET/CT system. METHODS: The image-quality phantom with (b-NEMA-IQ, BMI = 29.2 kg/m2) and without (NEMA-IEC, BMI = 21.4 kg/m2) a 'belt' of water-bags was filled with 18F-FDG activities to obtain nominal standardized uptake values (SUV) of 19, 8 and 5. Patients with BMI ≤ 25 kg/m2 (L-BMI) and BMI > 25 kg/m2 (H-BMI) were enrolled in this study. Phantom and patients underwent list-mode PET acquisition at 120 s/bed-position. Images reconstructed with clinical protocol and different ESD (120, 90, 75, 60, 45, 30 s) were analysed for comparison of maximum SUV (SUVmax), maximum standardized uptake value lean-body-mass corrected (SULmax) and noise. RESULTS: 79 oncologic patients (45 L-BMI, 44 H-BMI) were analysed. From 90 s to 30 s, an increasing variation of SUVmax and SULmax with respect to the reference 120 s time was observed, from 18% to 60% and from 16% to 37% for phantom and patients, respectively. SUVmax values were significantly higher (+50%) in b-NEMA-IQ than NEMA-IQ phantom and in H-BMI (+33%) than L-BMI patients. No significant difference was found in SULmax for the two BMI categories in both phantom and patients. CV values decreased when increasing ESD, being higher in H-BMI patients (0.13-0.25) and b-NEMA-IQ phantom (0.15-0.28) than in L-BMI patients (0.11-0.21) and NEMA-IQ phantom (0.11-0.20). CONCLUSIONS: Reduction of ESD may severely impact on the variations of SUVmax and SULmax in 18F-FDG PET/CT imaging. This study confirms recommendations of using SUL for lesion uptake quantification, being unaffected by BMI variation.

ITA-IMMUNO-PET: The Role of [18F]FDG PET/CT for Assessing Response to Immunotherapy in Patients with Some Solid Tumors.

AIM: To examine the role of [18F]FDG PET/CT for assessing response to immunotherapy in patients with some solid tumors. METHODS: Data recorded in a multicenter (n = 17), retrospective database between March and November 2021 were analyzed. The sample included patients with a confirmed diagnosis of a solid tumor who underwent serial [18F]FDG PET/CT (before and after one or more cycles of immunotherapy), who were >18 years of age, and had a follow-up of at least 12 months after their first PET/CT scan. Patients enrolled in clinical trials or without a confirmed diagnosis of cancer were excluded. The authors classified cases as having a complete or partial metabolic response to immunotherapy, or stable or progressive metabolic disease, based on a visual and semiquantitative analysis according to the EORTC criteria. Clinical response to immunotherapy was assessed at much the same time points as the serial PET scans, and both the obtained responses were compared. RESULTS: The study concerned 311 patients (median age: 67; range: 31-89 years) in all. The most common neoplasm was lung cancer (56.9%), followed by malignant melanoma (32.5%). Nivolumab was administered in 46.3%, and pembrolizumab in 40.5% of patients. Baseline PET and a first PET scan performed at a median 3 months after starting immunotherapy were available for all 311 patients, while subsequent PET scans were obtained after a median 6, 12, 16, and 21 months for 199 (64%), 102 (33%), 46 (15%), and 23 (7%) patients, respectively. Clinical response to therapy was recorded at around the same time points after starting immunotherapy for 252 (81%), 173 (56%), 85 (27%), 40 (13%), and 22 (7%) patients, respectively. After a median 18 (1-137) months, 113 (36.3%) patients had died. On Kaplan-Meier analysis, metabolic responders on the first two serial PET scans showed a better prognosis than non-responders, while clinical response became prognostically informative from the second assessment after starting immunotherapy onwards. CONCLUSIONS: [18F]FDG PET/CT could have a role in the assessment of response to immunotherapy in patients with some solid tumors. It can provide prognostic information and thus contribute to a patient's appropriate treatment. Prospective randomized controlled trials are mandatory.

Can Baseline [18F]FDG PET/CT Predict Response to Immunotherapy After 6 Months and Overall Survival in Patients with Lung Cancer or Malignant Melanoma? A Multicenter Retrospective Study.

Aim: To assess the role of baseline 18F-fluorodeoxyglucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in predicting response to immunotherapy after 6 months and overall survival (OS) in patients with lung cancer (LC) or malignant melanoma (MM). Materials and Methods: Data from a multicenter, retrospective study conducted between March and November 2021 were analyzed. Patients >18 years old with a confirmed diagnosis of LC or MM, who underwent a baseline [18F]FDG-PET/CT within 1-2 months before starting immunotherapy and had a follow-up of at least 12 months were included. PET scans were examined visually and semiquantitatively by physicians at peripheral centers. The metabolic tumor burden (number of lesions with [18F]FDG-uptake) and other parameters were recorded. Clinical response was assessed at 3 and 6 months after starting immunotherapy, and OS was calculated as the time elapsing between the PET scan and death or latest follow-up. Results: The study concerned 177 patients with LC and 101 with MM. Baseline PET/CT was positive in primary or local recurrent lesions in 78.5% and 9.9% of cases, in local/distant lymph nodes in 71.8% and 36.6%, in distant metastases in 58.8% and 84%, respectively, in LC and in MM patients. Among patients with LC, [18F]FDG-uptake in primary/recurrent lung lesions was more often associated with no clinical response to immunotherapy after 6 months than in cases without any tracer uptake. After a mean 21 months, 46.5% of patients with LC and 37.1% with MM had died. A significant correlation emerged between the site/number of [18F]FDG foci and death among patients with LC, but not among those with MM. Conclusions: In patients with LC who are candidates for immunotherapy, baseline [18F]FDG-PET/CT can help to predict response to this therapy after 6 months, and to identify those with a poor prognosis based on their metabolic parameters. For patients with MM, there was only a weak correlation between baseline PET/CT parameters, response to therapy, and survival.

Value of 18F-fluorocholine PET/CT in predicting response to radical radiotherapy in patients with localized prostate cancer.

PURPOSE: This study aims to establish whether metabolic parameters obtainable from FCH PET/CT can predict long-term response to radical radiotherapy (rRT) in patients with localized prostate cancer (PCa). METHODS: Drawing on a single-center database, we retrospectively reviewed the pre-treatment FCH PET/CT scans of 50 patients who underwent rRT between 2012 and 2017. Patients were enrolled if they had a follow-up of at least 3 years after rRT. Various metabolic parameters were considered for each PET/CT, including FCH multifocality. rRT was administered to all patients for a total equivalent dose of 76-80 Gy, using a standard or hypofractionated schedule. Patients were classified as disease-free (DF) if their PSA levels after rRT rose by <2 ng/mL vis-à-vis their PSA nadir, or as not disease free (NDF) if their PSA levels rose by more than 2 ng/ml. RESULTS: A multifocal FCH uptake in the prostate gland was identified in 27 patients (54%). At 3-year follow-up, 37 patients (74%) were judged DF, and 13 (26%) were NDF. The SUVmax and SUVmean, and the sum of the two values in all FCH foci in the prostate gland were significantly higher for NDF patients than for DF patients (all p < 0.005). The sum of the TLCKA levels in all FCH foci was likewise significantly higher in patients who were NDF than in those found DF (median 54.5 vs. 29.4; p < 0.05). At univariate analysis, the most of PET-metrics and Gleason Score were predictors of biochemical relapse after 3-year follow-up (all p < 0.05). CONCLUSION: Higher SUVs seems predict a worse outcome for patients with multifocal intraprostatic lesions who are candidates for rRT.

Novel Nuclear Medicine Imaging Applications in Immuno-Oncology.

The global immuno-oncology pipeline has grown progressively in recent years, leading cancer immunotherapy to become one of the main issues of the healthcare industry. Despite their success in the treatment of several malignancies, immune checkpoint inhibitors (ICIs) perform poorly in others. Again, ICIs action depends on such a multitude of clinico-pathological features, that the attempt to predict responders/long-responders with ad-hoc built immunograms revealed to be quite complex. In this landscape, the role of nuclear medicine might be crucial, with first interesting evidences coming from small case series and pre-clinical studies. Positron-emission tomography (PET) techniques provide functional information having a predictive and/or prognostic value in patients treated with ICIs or adoptive T-cell therapy. Recently, a characterization of the tumor immune microenvironment (TiME) pattern itself has been shown to be feasible through the use of different radioactive tracers or image algorithms, thus adding knowledge about tumor heterogeneity. Finally, nuclear medicine exams permit an early detection of immune-related adverse events (irAEs), with on-going clinical trials investigating their correlation with patients' outcome. This review depicts the recent advances in molecular imaging both in terms of non-invasive diagnosis of TiME properties and benefit prediction from immunotherapeutic agents.

18F-FDG PET/CT in non-small-cell lung cancer patients: a potential predictive biomarker of response to immunotherapy.

AIM: The aim of this study was to assess the predictive role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in the evaluation of response to immunotherapy in patients affected by metastatic lung cancer. MATERIALS AND METHODS: From a single-center database, data for 32 patients (median age: 69 years; range: 37-78) with metastatic lung cancer were retrospectively retrieved. All patients were treated with nivolumab. PD-L1 expression was available in 19/32 patients. All patients underwent F-FDG PET/CT before immunotherapy. Whole-body maximum standardized uptake value (SUVmaxwb), metabolic tumor volume (MTVwb), and total lesion glycolysis (TLGwb) were obtained as the sum of SUVmax, metabolic tumor volume, and total lesion glycolysis in all metabolic lesions. The best response to therapy was considered in terms of partial response (PR), stable disease (SD), and progressive disease (PD) on the basis of clinical and radiological follow-up. RESULTS: F-FDG PET/CT was positive in 30/32 (94%) patients. The majority of them had a pathological F-FDG uptake in the lung, lymph nodes, and bones. SUVmaxwb, MTVwb, and TLGwb were higher in patients with a positive PD-L1 expression than those with negative expression. Twenty-one patients achieved disease control (PR+SD), whereas 11 did not (PD). SUVmaxwb was significantly higher in patients without a response to therapy than those with a response to immunotherapy (median: 48.97 vs. 20.85; Student t-test: P = 0.002). Similarly, TLGwb and MTVwb were also higher in nonresponders than responders, although not statistically significant. However, the difference was more evident in women than men (median SUVmaxwb in responders and nonresponders for women and men: 17.86 vs. 85.89 and 21.38 vs. 44.38, respectively). CONCLUSION: The entire tumor burden evaluated by F-FDG PET/CT can be predictive of response to immunotherapy in patients with metastatic lung cancer. A large prospective multicenter trial is warranted to definitively assess the usefulness of F-FDG PET/CT as a predictive biomarker of response to immunotherapy.

18F-Choline PET/CT in Leptomeningeal Breast Cancer Metastases.

We describe a case of 47-year-old woman affected by human epidermal growth factor receptor-2-positive breast cancer with a diffuse leptomeningeal carcinomatosis. An intense uptake of F-choline was reported at fused PET/MRI images in the brain, compatible with a diffuse leptomeningeal disease. This case highlights that F-choline PET would be used for the identification of leptomeningeal involvement in patients affected by breast cancer, as a support of MRI images.

Comparison Between 18F-Dopa and 18F-Fet PET/CT in Patients with Suspicious Recurrent High Grade Glioma: A Literature Review and Our Experience.

PURPOSES: The aims of the present study were to: 1- critically assess the utility of L-3,4- dihydroxy-6-18Ffluoro-phenyl-alanine (18F-DOPA) and O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) Positron Emission Tomography (PET)/Computed Tomography (CT) in patients with high grade glioma (HGG) and 2- describe the results of 18F-DOPA and 18F-FET PET/CT in a case series of patients with recurrent HGG. METHODS: We searched for studies using the following databases: PubMed, Web of Science and Scopus. The search terms were: glioma OR brain neoplasm and DOPA OR DOPA PET OR DOPA PET/CT and FET OR FET PET OR FET PET/CT. From a mono-institutional database, we retrospectively analyzed the 18F-DOPA and 18F-FET PET/CT of 29 patients (age: 56 ± 12 years) with suspicious for recurrent HGG. All patients underwent 18F-DOPA or 18F-FET PET/CT for a multidisciplinary decision. The final definition of recurrence was made by magnetic resonance imaging (MRI) and/or multidisciplinary decision, mainly based on the clinical data. RESULTS: Fifty-one articles were found, of which 49 were discarded, therefore 2 studies were finally selected. In both the studies, 18F-DOPA and 18F-FET as exchangeable in clinical practice particularly for HGG patients. From our institutional experience, in 29 patients, we found that sensitivity, specificity and accuracy of 18F-DOPA PET/CT in HGG were 100% (95% confidence interval- 95%CI - 81-100%), 63% (95%CI: 39-82%) and 62% (95%CI: 39-81%), respectively. 18F-FET PET/CT was true positive in 4 and true negative in 4 patients. Sensitivity, specificity and accuracy for 18F-FET PET/CT in HGG were 100%. CONCLUSION: 18F-DOPA and 18F-FET PET/CT have a similar diagnostic accuracy in patients with recurrent HGG. However, 18F-DOPA PET/CT could be affected by inflammation conditions (false positive) that can alter the final results. Large comparative trials are warranted in order to better understand the utility of 18F-DOPA or 18F-FET PET/CT in patients with HGG.

Performance evaluation of a new time of flight PET/CT scanner: Results of a multicenter study.

PURPOSE: The aim of this multicenter study was to evaluate the performance of the upgraded version of the Ingenuity TF PET/CT scanner, according to the NEMA NU-2 2012 standards. METHODS: Spatial resolution, sensitivity, count rate response, scatter fraction, image quality and accuracy were evaluated on three Ingenuity TF scanners installed in Italian hospitals. Furthermore, energy and timing resolution were measured. A detailed image quality phantom analysis was performed to evaluate the effect of different clinical reconstruction parameters, including the application of PSF correction. RESULTS: Results show an average spatial resolution of 4.7 mm and an average absolute system sensitivity of 7.9 cps/kBq. The average maximum NECR was 119.83 kcps at 20.67 kBq/ml, while the maximum true event rate was 322.62 kcps at the concentration of 24.51 kBq/ml. The average maximum bias below NECR peak was 12.58%. All the results of NEMA tests were in agreement with the values declared by the manufacturer. The estimated average energy and timing resolution were 10.83% and 536.2 ps, respectively. Image quality phantom analysis obtained with different reconstruction settings showed that PSF correction was the parameter that affected mainly on contrast recovery coefficient, while the iteration number and amplitude of Gaussian filter had no significant effect. Of relevance, the application of PSF correction never led to recovery coefficient values higher than 100% and to Gibbs or edge artifacts. CONCLUSIONS: The new Ingenuity TF model shows physical performance similar to other scanners of the latest generation for all standard NEMA NU2-2012 measurements.

The Role of 18F-FDG PET/CT in Staging and Prognostication of Mantle Cell Lymphoma: An Italian Multicentric Study.

Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with poor prognosis in which 18F-FDG-PET/CT role in treatment response evaluation and prediction of outcome is still unclear. The aim of this multicentric study was to investigate the role of 18F-FDG-PET/CT in staging MCL and the prognostic role of Deauville criteria (DC) in terms of progression-free survival (PFS) and overall survival (OS). We retrospectively enrolled 229 patients who underwent baseline and end-of-treatment (eot) 18F-FDG-PET/CT after first-line therapy. EotPET/CT scans were visually interpreted according to DC. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for evaluation of bone marrow (BM) were 27%, 100%, 100%, 48% and 57%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for evaluation of the gastrointestinal (GI) tract were 60%, 99%, 93%, 90% and 91%, respectively. At a median follow-up of 40 months, relapse occurred in 104 cases and death in 49. EotPET/CT results using DC significantly correlated with PFS, not with OS. Instead, considering OS, only MIPI score was significantly correlated. In conclusion, we demonstrated that MCL is an FDG-avid lymphoma and 18F-FDG-PET/CT is a useful tool for staging purpose, showing good specificity for BM and GI evaluation, but suboptimal sensitivity. EotPET/CT result was the only independent significant prognostic factor that correlated with PFS.

Prognostic and diagnostic value of [18F]FDG-PET/CT in restaging patients with small cell lung carcinoma: an Italian multicenter study.

BACKGROUND: The presence of residual disease after initial treatment in small cell lung cancer (SCLC) influences prognosis and impacts patient management. To date, few data exist on the value of fluorine-18-fluorodeoxyglucose ([F]FDG)-PET/computed tomography (CT) in SCLC at restaging. Therefore, in restaging patients with SCLC, we aimed to (a) evaluate the prognostic value yielded by [F]FDG-PET/CT and (b) assess the diagnostic agreement between [F]FDG-PET/CT and contrast-enhanced computed tomography (ceCT). PATIENTS AND METHODS: From a multicenter database, we evaluated 164 patients with SCLC who underwent [F]FDG-PET/CT for restaging purposes. PET scans were evaluated visually to identify the presence of recurrence. For each patient, the maximum and the mean standardized uptake value (SUVmax and SUVmean, respectively), metabolic tumor volume, and total lesion glycolysis were calculated, taking into account the lesion with the highest [F]FDG uptake (namely, the index lesion) in the local recurrences, lymph node involvement, and distant metastasis categories. Kaplan-Meier curves were computed to assess the effects of [F]FDG-PET/CT findings on overall survival (OS) and progression-free survival. Furthermore, the agreement between PET/CT and ceCT in detecting metastases was evaluated in 119 patients on a patient-based analysis (Cohen's κ; P < 0.05). RESULTS: The presence of metastatic lesions at [F]FDG-PET/CT was associated with a significantly shorter OS (P = 0.039) and progression-free survival (P < 0.001). Higher SUVmax showed a trend toward a shorter OS (P = 0.065). The K-agreement between ceCT and PET/CT in recurrent SCLC was 0.37 (P < 0.001). PET/CT and ceCT showed the same number of lesions in 52 (43.7%) patients, whereas PET/CT detected additional lesions in 35 (29.4%) patients. CONCLUSION: Detection of metastatic lesions at restaging by [F]FDG-PET/CT can predict a higher rate of progression and negatively influence OS in patients with SCLC. [F]FDG-PET/CT and ceCT seem to be complementary imaging modalities in patients with metastatic SCLC.

Ectopic Salivary Gland in a Patient With Prostate Cancer at 18F-Choline PET/CT: An Incidental Finding.

A 65-year-old man with prostate cancer surgically treated in June 2016 underwent F-choline PET/CT in April 2017 for a biochemical recurrence of disease. PET/CT revealed a high tracer uptake in a solid nodulation near the left masseter muscle with a high SUVmax. The patient underwent both ultrasonography examination and fine needle aspiration cytology that confirmed the presence of an ectopic salivary gland. This case highlights that, in patients undergoing choline PET/CT, a careful analysis of the physiological biodistribution should be made by considering also the presence of accessory salivary glands.

Oligometastatic recurrent prostate cancer detects by fluorine-18-choline positron emission tomography/computed tomography in patients with prostate-specific antigen levels of up to 5 ng/ml.

PURPOSE: The aim of this study was to assess the ability of fluorine-18-fluorocholine (F-FCH) PET/computed tomography (CT) to detect oligometastatic disease (OMD) in patients with early recurrence of prostate cancer (PC) [prostate-specific antigen (PSA)≤5 ng/ml]. PATIENTS AND METHODS: Between 2010 and 2016, 324 patients with PC and PSA levels of less than or equal to 5 ng/ml were recruited. The mean (SD) age of the patients was 71 (10) years. All patients were treated with a radical prostatectomy±lymphadenectomy. One-hundred and twenty-one patients were under hormonal therapy at the time of PET/CT, whereas 203 were not. The mean (SD) PSA at the time of PET/CT was 1.33 (1.19) ng/ml, the mean (SD) PSA doubling time (PSAdt) was 10 (12) months, and the mean (SD) PSA velocity (PSAvel) was 1.94 (3.31) ng/ml/year. The correlation between continuous and categorical data was assessed using Student's t-test or by analysis of variance and by the χ-test, respectively. Univariate and multivariate analysis was carried out for the identification of clinical variables able to predict the presence of OMD. RESULTS: One-hundred and ninety-three patients had a negative F-FCH PET/CT, whereas 131 (40.4%) had a positive scan. Of these latter patients, 35 had a significant F-FCH uptake in the prostatic fossae, 59 in the lymph nodes, and 37 in bone. PSA levels were significantly different between patients with a positive than those with a negative scan (P<0.001). F-FCH PET/CT was negative in the majority of patients with a PSA of less than or equal to 1 (63.2%) ng/ml. More than 60% of patients with a PSAdt of less than or equal to 6 months had a positive F-FCH PET/CT scan for OMD. PSAvel was higher in patients with a positive scan than those with a negative finding. At univariate analysis, PSA level, PSAdt, and PSAvel were predictors of a positive F-FCH PET/CT for OMD, whereas on multivariate analysis, only PSA level and PSAdt were independent predictors (both P<0.01). Furthermore, PSAdt was the only independent predictor of OMD at the lymph node level. CONCLUSION: In patients with early recurrence of PC, F-FCH PET/CT is able to detect OMD in 40% of cases. This finding has an important impact on the detection of PC recurrent lesions that could be treated by local therapy to achieve long-term survival or cure.