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Unspecific bone uptake (UBU) related to [ 18 F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [ 18 F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [ 18 F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUV max , SUV mean , PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HU mean ) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less ( n = 2) or more ( n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake ( n = 178) as PCa metastases or not. Results: In total, 448 bone [ 18 F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT ( P < 0.001) with determination of SUV max ( P < 0.001) and HU mean ( P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation ( n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score's AUC was significantly higher than that of HU mean (AUC, 0.62) and remained high among lesions with HU mean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [ 18 F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein overexpressed on the surface of tumor cells in most of the patients affected by prostate adenocarcinoma (PCa). However, PSMA expression has also been demonstrated in the endothelial cells of newly formed vessels of various solid tumors, suggesting a role for PSMA in neoangiogenesis. In this scenario, gallium-68 ( 68 Ga) or fluoro-18 ( 18 F)-labeled PSMA positron emission tomography (PET) may play a role in tumors other than PCa, generally evaluated employing other radiopharmaceuticals targeting different pathways. This review aims to investigate the detection rate of PSMA-PET compared to other radiopharmaceuticals (especially [ 18 F]FDG) in non-prostate tumors to identify patients who may benefit from the use of such a theragnostic agent., Methods: We performed a bibliographic search on three different databases until February 2024 using the following terms: "positron emission tomography", "PET", "PET/CT", "Prostate-specific membrane antigen", "PSMA", "non-prostate", "not prostate cancer", "solid tumor", "FDG", "Fluorodeoxyglucose", "FAPi", "FET", "MET", "DOPA", "choline", "FCH", "FES", "DOTATOC", "DOTANOC", and "DOTATATE". Only original articles edited in English with at least 10 patients were included., Results: Out of a total of 120 articles, only 25 original articles comparing PSMA with other radiotracers were included in this study. The main evidence was demonstrated in renal cell carcinoma, where PSMA showed a higher detection rate compared to [ 18 F]FDG PET/CT, with implications for patient management. PSMA PET may also improve the assessment of other entities, such as gliomas, in defining regions of early neoangiogenesis. Further data are needed to evaluate the potential role of PSMA-PET in triple-negative breast cancer as a novel therapeutic vascular target. Finally, unclear applications of PSMA-PET include thyroid and gastrointestinal tumors., Conclusions: The present review shows the potential use of PSMA-labeled PET/CT in solid tumors beyond PCa, underlining its value over other radiopharmaceuticals (mainly [ 18 F]FDG). Prospective clinical trials with larger sample sizes are crucial to further investigate these possible clinical applications.

A 79-year-old man with prostate cancer (PCa) was referred to our center to perform a [ 11 C]Choline PET/CT for biochemical recurrence. Positron emission tomography/computed tomography (PET/CT) scan detected PCa recurrence in the prostate gland and several pelvic and abdominal lymph nodes. Two abnormal uptakes were also identified in the right breast and in the liver, respectively. Breast histological findings turned out to be gynecomastia, while the liver lesion resulted in a benign perfusion anomaly at follow-up magnetic resonance imaging (MRI). Although incidental findings were benign in this case, it is important to always investigate abnormal uptakes of [ 11 C]Choline, as it could be an expression of further metastases or synchronous malignancies such as breast cancer and hepatocellular carcinoma., Competing Interests: Conflict of InterestVirginia Liberini, Simona Peano, Emanuele Fabbro, Riccardo Laudicella, Alberto Papaleo, and Michele Balma declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Korean Society of Nuclear Medicine 2023.)

Nuclear medicine has acquired a crucial role in the management of patients with neuroendocrine neoplasms (NENs) by improving the accuracy of diagnosis and staging as well as their risk stratification and personalized therapies, including radioligand therapies (RLT). Artificial intelligence (AI) and radiomics can enable physicians to further improve the overall efficiency and accuracy of the use of these tools in both diagnostic and therapeutic settings by improving the prediction of the tumor grade, differential diagnosis from other malignancies, assessment of tumor behavior and aggressiveness, and prediction of treatment response. This systematic review aims to describe the state-of-the-art AI and radiomics applications in the molecular imaging of NENs.

The aim of this review is to provide a comprehensive overview of the existing literature concerning the applications of positron emission tomography (PET) radiomics in lung cancer patient candidates or those undergoing immunotherapy., Materials and Methods: A systematic review was conducted on databases and web sources. English-language original articles were considered. The title and abstract were independently reviewed to evaluate study inclusion. Duplicate, out-of-topic, and review papers, or editorials, articles, and letters to editors were excluded. For each study, the radiomics analysis was assessed based on the radiomics quality score (RQS 2.0). The review was registered on the PROSPERO database with the number CRD42023402302., Results: Fifteen papers were included, thirteen were qualified as using conventional radiomics approaches, and two used deep learning radiomics. The content of each study was different; indeed, seven papers investigated the potential ability of radiomics to predict PD-L1 expression and tumor microenvironment before starting immunotherapy. Moreover, two evaluated the prediction of response, and four investigated the utility of radiomics to predict the response to immunotherapy. Finally, two papers investigated the prediction of adverse events due to immunotherapy., Conclusions: Radiomics is promising for the evaluation of TME and for the prediction of response to immunotherapy, but some limitations should be overcome.

Aim: To assess the role of baseline 18 F-fluorodeoxyglucose ([ 18 F]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 [ 18 F]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 [ 18 F]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, [ 18 F]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 [ 18 F]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 [ 18 F]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.

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.

Background: Breast cancer is the most common malignancy in women, with high morbidity and mortality. Molecular alterations in breast cancer involve the expression or upregulation of various molecular targets that can be used for diagnostic nuclear medicine imaging and radiopharmaceutical treatment. Theragnostics is based on the binding of radionuclides to molecular targets. These radionuclides can induce a cytotoxic effect on the specific tumor cell (target) or its vicinity, thus allowing a personalized approach to patients with effective treatment and comparably small side effects., Aim: This review aims to describe the most promising molecular targets currently under investigation for theragnostics and precision oncology in breast cancer., Methods: A comprehensive literature search of studies on theragnostics in breast cancer was performed in the PubMed, PMC, Scopus, Google Scholar, Embase, Web of Science, and Cochrane library databases, between 2010 and 2022, using the following terms: breast neoplasm*, breast, breast cancer*, theragnostic*, theranostic*, radioligand therap*, RLT, MET, FLT, FMISO, FES, estradiol, trastuzumab, PD-L1, PSMA, FAPI, FACBC, fluciclovine, FAZA, GRPR, DOTATOC, DOTATATE, CXC4, endoglin, gastrin, mucin1, and syndecan1., Results: Fifty-three studies were included in the systematic review and summarized in six clinical sections: 1) human epidermal growth factor receptor 2 (HER2); 2) somatostatin receptors (SSTRS); 3) prostate-specific membrane antigen radiotracers (PSMA); 4) fibroblast activation protein-α targeted radiotracers; 5) gastrin-releasing peptide receptor-targeted radiotracers; 6) other radiotracers for theragnostics., Conclusion: The theragnostic approach will progressively allow better patient selection, and improve the prediction of response and toxicity, avoiding unnecessary and costly treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alveolar echinococcosis is a rare parasitic disease, most frequently affecting the liver, as a slow-growing tumor-like lesion. If inoperable, long-term benzimidazole therapy is required, which is associated with high healthcare costs and occasionally with increased morbidity. The aim of our study was to determine the role 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in staging of patients with alveolar echinococcosis and to identify quantitative imaging parameters related to patient outcome and/or duration of benzimidazole therapy. In this single-center retrospective cohort study, 47 PET/CT performed for staging in patients with confirmed alveolar echinococcosis were analysed. In 43 patients (91%) benzimidazole therapy was initiated and was successfully stopped after a median of 870 days (766-2517) in 14/43 patients (33%). In inoperable patients, tests for trend of survivor functions displayed clear trends for longer benzimidazole therapy duration (p = 0.05; n = 25), and for longer time intervals to reach non-detectable serum concentration of Em-18 antibodies (p = 0.01, n = 15) across tertiles of SUVratio (maximum standardized uptake value in the echinococcus manifestation compared to normal liver tissue). Hence, in inoperable patients with alveolar echinococcosis, PET/CT performed for staging may predict the duration of benzimidazole therapy., (© 2022. The Author(s).)

Our objective was to evaluate the prognostic value of somatostatin receptor tumor burden on 68 Ga-DOTATOC PET/CT in patients with well-differentiated (WD) neuroendocrine tumors (NETs). Methods: We retrospectively analyzed the 68 Ga-DOTATOC PET/CT scans of 84 patients with histologically confirmed WD NETs (51 grade 1, 30 grade 2, and 3 grade 3). For each PET/CT scan, all 68 Ga-DOTATOC-avid lesions were independently segmented by 2 operators using a customized threshold based on the healthy liver SUV max (LIFEx, version 5.1). Somatostatin receptor-expressing tumor volume (SRETV) and total lesion somatostatin receptor expression (TLSRE = SRETV × SUV mean ) were extracted for each lesion, and then whole-body SRETV and TLSRE (SRETVwb and TLSREwb, respectively) were defined as the sum of SRETV and TLSRE, respectively, for all segmented lesions in each patient. Time to progression (TTP) was defined as the combination of disease-free survival in patients undergoing curative surgery ( n  = 10) and progression-free survival for patients with unresectable or metastatic disease ( n  = 74). TTP and overall survival were calculated by Kaplan-Meier analysis, log-rank testing, and the Cox proportional-hazards regression model. Results: After a median follow-up of 15.5 mo, disease progression was confirmed in 35 patients (41.7%) and 14 patients died. A higher SRETVwb (>39.1 cm 3 ) and TLSREwb (>306.8 g) correlated significantly with a shorter median TTP (12 mo vs. not reached; P < 0.001). In multivariate analysis, SRETVwb ( P  = 0.005) was the only independent predictor of TTP regardless of histopathologic grade and TNM staging. Conclusion: According to our results, SRETVwb and TLSREwb extracted from 68 Ga-DOTATOC PET/CT could predict TTP or overall survival and might have important clinical utility in the management of patients with WD NETs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background/aim: Prostate-specific-membrane-antigen/positron emission tomography (PSMA-PET) detects with high accuracy disease-recurrence, leading to changes in the management of biochemically-recurrent (BCR) prostate cancer (PCa). However, data regarding the oncological outcomes of patients who performed PSMA-PET are needed. The aim of this study was to evaluate the incidence of clinically relevant events during follow-up in patients who performed PSMA-PET for BCR after radical treatment., Materials and Methods: This analysis included consecutive, hormone-sensitive, hormone-free, recurrent PCa patients (HSPC) enrolled through a prospective study. All patients were eligible for salvage therapy, having at least 24 months of follow-up after PSMA-PET. The primary endpoint was the Event-Free Survival (EFS), defined as the time between the PSMA-PET and the date of event/last follow-up. The Kaplan-Meier method was used to estimate the EFS curves. EFS was also investigated by Cox proportional hazards regression. Events were defined as death, radiological progression, or PSA recurrence after therapy., Results: One-hundred and seventy-six (n = 176) patients were analyzed (median PSA 0.62 [IQR: 0.43-1.00] ng/mL; median follow-up of 35.4 [IQR: 26.5-40.3] months). The EFS was 78.8% at 1 year, 65.2% (2 years), and 52.2% (3 years). Patients experiencing events during study follow-up had a significantly higher median PSA (0.81 [IQR: 0.53-1.28] vs 0.51 [IQR: 0.36-0.80] ng/mL) and a lower PSA doubling time (PSAdt) (5.4 [IQR: 3.7-11.6] vs 12.7 [IQR: 6.6-24.3] months) (p < 0.001) compared to event-free patients. The Kaplan-Meier curves showed that PSA > 0.5 ng/mL, PSAdt ≤ 6 months, and a positive PSMA-PET result were associated with a higher event rate (p < 0.01). No significant differences of event rates were observed in patients who received changes in therapy management after PSMA-PET vs. patients who did not receive therapy changes. Finally, PSA > 0.5 ng/mL and PSAdt ≤ 6 months were statistically significant event-predictors in multivariate model (p < 0.001)., Conclusion: Low PSA and long PSAdt were significant predictors of longer EFS. A lower incidence of events was observed in patients having negative PSMA-PET, since longer EFS was significantly more probable in case of a negative scan., (© 2022. The Author(s).)

In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients' risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these "big data" in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer., (© 2022. The Author(s) under exclusive licence to European Society of Radiology.)

The aim of the study was to analyze the use of block sequential regularized expectation maximization (BSREM) with different β-values for the detection of brain metastases in digital fluorine-18 labeled 2-deoxy-2-fluoro-D-glucose (18F-FDG) PET/CT in lung cancer patients. We retrospectively analyzed staging/restaging 18F-FDG PET/CT scans of 40 consecutive lung cancer patients with new brain metastases, confirmed by MRI. PET images were reconstructed using BSREM (β-values of 100, 200, 300, 400, 500, 600, 700) and OSEM. Two independent blinded readers (R1 and R2) evaluated each reconstruction using a 4-point scale for general image quality, noise, and lesion detectability. SUVmax of metastases, brain background, target-to-background ratio (TBR), and contrast recovery (CR) ratio were recorded for each reconstruction. Among all reconstruction techniques, differences in qualitative parameters were analyzed using non-parametric Friedman test, while differences in quantitative parameters were compared using analysis of variances for repeated measures. Cohen's kappa (k) was used to measure inter-reader agreement. The overall detectability of brain metastases was highest for BSREM200 (R1: 2.83 ± 1.17; R2: 2.68 ± 1.32) and BSREM300 (R1: 2.78 ± 1.23; R2: 2.68 ± 1.36), followed by BSREM100, which had lower accuracy owing to noise. The highest median TBR was found for BSREM100 (R1: 2.19 ± 1.05; R2: 2.42 ± 1.08), followed by BSREM200 and BSREM300. Image quality ratings were significantly different among reconstructions (p < 0.001). The median quality score was higher for BSREM100-300, and both noise and metastases' SUVmax decreased with increasing β-value. Inter-reader agreement was particularly high for the detectability of photopenic metastases and blurring (all k > 0.65). BSREM200 and BSREM300 yielded the best results for the detection of brain metastases, surpassing both BSREM400 and OSEM, typically used in clinical practice., (© 2022. The Author(s).)

Despite impressive results, almost 30% of NET do not respond to PRRT and no well-established criteria are suitable to predict response. Therefore, we assessed the predictive value of radiomics [ 68 Ga]DOTATOC PET/CT images pre-PRRT in metastatic GEP NET. We retrospectively analyzed the predictive value of radiomics in 324 SSTR-2-positive lesions from 38 metastatic GEP-NET patients (nine G1, 27 G2, and two G3) who underwent restaging [ 68 Ga]DOTATOC PET/CT before complete PRRT with [ 177 Lu]DOTATOC. Clinical, laboratory, and radiological follow-up data were collected for at least six months after the last cycle. Through LifeX, we extracted 65 PET features for each lesion. Grading, PRRT number of cycles, and cumulative activity, pre- and post-PRRT CgA values were also considered as additional clinical features. [ 68 Ga]DOTATOC PET/CT follow-up with the same scanner for each patient determined the disease status (progression vs. response in terms of stability/reduction/disappearance) for each lesion. All features (PET and clinical) were also correlated with follow-up data in a per-site analysis (liver, lymph nodes, and bone), and for features significantly associated with response, the Δradiomics for each lesion was assessed on follow-up [ 68 Ga]DOTATOC PET/CT performed until nine months post-PRRT. A statistical system based on the point-biserial correlation and logistic regression analysis was used for the reduction and selection of the features. Discriminant analysis was used, instead, to obtain the predictive model using the k-fold strategy to split data into training and validation sets. From the reduction and selection process, HISTO&#95;Skewness and HISTO&#95;Kurtosis were able to predict response with an area under the receiver operating characteristics curve (AUC ROC), sensitivity, and specificity of 0.745, 80.6%, 67.2% and 0.722, 61.2%, 75.9%, respectively. Moreover, a combination of three features (HISTO&#95;Skewness; HISTO&#95;Kurtosis, and Grading) did not improve the AUC significantly with 0.744. SUV max , however, could not predict the response to PRRT ( p = 0.49, AUC 0.523). The presented preliminary "theragnomics" model proved to be superior to conventional quantitative parameters to predict the response of GEP-NET lesions in patients treated with complete [ 177 Lu]DOTATOC PRRT, regardless of the lesion site.

Background: The aim of this study was to assess the relationship between the histopathological properties of hyperfunctioning parathyroids and parathyroid 18F-choline uptake., Patients and Methods: A total of 31 parathyroid adenomas were retrospectively analyzed in patients with primary hyperparathyroidism and preoperative 18F-choline PET/MR. PET/MR parameters of parathyroid glands (SUVmax and target-to-background ratio in early-phase [EP] and late-phase [LP]), MRI volume, preoperative parathyroid hormone (PTH) serum concentration, and postoperative histopathology (predominant cell type and growth pattern of adenoma cells, location and size of adenoma) were assessed. The relationship of PET/MR parameters, PTH, and histological parameters was determined using linear regression, Spearman correlation and Kruskal-Wallis test., Results: The median volume of parathyroid adenoma was 421.78 ± 142.46 mm3 (46.39-4412.69). Adenomas were predominantly composed of chief, water-clear, and oncocytic/oxyphilic cells in 27/31, 2/31, and 2/31 cases, respectively. The growth pattern was predominantly solid, follicular, and trabecular in 18/31, 8/31, and 5/31, respectively. The SUVmax was 6.71 ± 3.39 in EP and 6.91 ± 3.97 in LP. Follicular growth pattern had slightly higher EP SUVmax (trabecular: 4.12 ± 0.56; solid: 6.62 ± 3.19; follicular: 8.56 ± 3.96; P = 0.046). Spearman correlation showed strong positive correlation between volume and both EP and LP SUVmax (0.626; P = 0.0001 and 0.576; P = 0.0001, respectively). Linear regression analysis revealed significant correlation between PTH level and EP and LP SUVmax (both P = 0.001); in contrast, no correlation was found between PTH level and both cell type and growth pattern., Conclusions: Our findings suggest that 18F-choline uptake of parathyroid adenomas might be associated both with the histological growth pattern and adenoma volume, but not with a specific cell type., Competing Interests: Conflicts of interest and sources of funding: M.W.H. is a recipient of speaker's fees and grants from GE Healthcare. Apart from that, the other authors of this manuscript declare no relationship with any companies, whose products or services may be related to the subject matter of the article. The University Hospital Zurich holds a research agreement with GE Healthcare (unrelated to the current study). M.W.H. is a recipient of grants for translational and clinical cardiac and oncological research from the Alfred and Annemarie von Sick legacy, and grants from the Artificial Intelligence in Oncological Imaging Network by the University of Zurich. No further specific grants from funding agencies in the public, commercial, or not-for-profit sectors were received for this study., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aim: To evaluate the association between baseline [18F]FDG-PET/CT tumor burden parameters and disease progression rate after first-line target therapy or immunotherapy in advanced melanoma patients., Materials and Methods: Forty four melanoma patients, who underwent [18F]FDG-PET/CT before first-line target therapy (28/44) or immunotherapy (16/44), were retrospectively analyzed. Whole-body and per-district metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. Therapy response was assessed according to RECIST 1.1 on CT scan at 3 (early) and 12 (late) months. PET parameters were compared using the Mann-Whitney test. Optimal cut-offs for predicting progression were defined using the ROC curve. PFS and OS were studied using Kaplan-Meier analysis., Results: Median (IQR) MTVwb and TLGwb were 13.1 mL and 72.4, respectively. Non-responder patients were 38/44, 26/28 and 12/16 at early evaluation, and 33/44, 21/28 and 12/16 at late evaluation in the whole-cohort, target, and immunotherapy subgroup, respectively. At late evaluation, MTVbone and TLGbone were higher in non-responders compared to responder patients (all p < 0.037) in the whole-cohort and target subgroup and MTVwb and TLGwb (all p < 0.022) in target subgroup. No significant differences were found for the immunotherapy subgroup. No metabolic parameters were able to predict PFS. Controversially, MTVlfn, TLGlfn, MTVsoft + lfn, TLGsoft + lfn, MTVwb and TLGwb were significantly associated (all p < 0.05) with OS in both the whole-cohort and target therapy subgroup., Conclusions: Higher values of whole-body and bone metabolic parameters were correlated with poorer outcome, while higher values of whole-body, lymph node and soft tissue metabolic parameters were correlated with OS.

Objectives: To evaluate the impact of fully automatic motion correction by data-driven respiratory gating (DDG) on positron emission tomography (PET) image quality, lesion detection and patient management., Materials and Methods: A total of 149 patients undergoing PET/CT for cancer (re-)staging were retrospectively included. Patients underwent a PET/CT on a digital detector scanner and for every patient a PET data set where DDG was enabled (PET DDG ) and as well as where DDG was not enabled (PET nonDDG ) was reconstructed. All PET data sets were evaluated by two readers which rated the general image quality, motion effects and organ contours. Further, both readers reviewed all scans on a case-by-case basis and evaluated the impact of PET DDG on additional apparent lesion, change of report, and change of management., Results: In 85% ( n = 126) of the patients, at least one bed position was acquired using DDG, resulting in mean scan time increase of 4:37 min per patient in the whole study cohort ( n = 149). General image quality was not rated differently for PET nonDDG and PET DDG images ( p = 1.000) while motion effects ( i.e. indicating general blurring) was rated significantly lower in PET DDG images and organ contours, including liver and spleen, were rated significantly sharper using PET DDG as compared to PET nonDDG (all p < 0.001). In 27% of patients, PET DDG resulted in a change of the report and in a total of 12 cases (8%), PET DDG resulted in a change of further clinical management., Conclusion: Deviceless DDG provided reliable fully automatic motion correction in clinical routine and increased lesion detectability and changed management in a considerable number of patients., Advances in Knowledge: DDG enables PET/CT with respiratory gating to be used routinely in clinical practice without external gating equipment needed.

Objectives: To compare block sequential regularized expectation maximization (BSREM) and ordered subset expectation maximization (OSEM) for the detection of in-transit metastasis (ITM) of malignant melanoma in digital [ 18 F]FDG PET/CT., Methods: We retrospectively analyzed a cohort of 100 [ 18 F]FDG PET/CT scans of melanoma patients with ITM, performed between May 2017 and January 2020. PET images were reconstructed with both OSEM and BSREM algorithms. SUVmax, target-to-background ratio (TBR), and metabolic tumor volume (MTV) were recorded for each ITM. Differences in PET parameters were analyzed with the Wilcoxon signed-rank test. Differences in image quality for different reconstructions were tested using the Man-Whitney U test., Results: BSREM reconstruction led to the detection of 287 ITM (39% more than OSEM). PET parameters of ITM were significantly different between BSREM and OSEM reconstructions (p < 0.001). SUVmax and TBR were higher (76.5% and 77.7%, respectively) and MTV lower (49.5%) on BSREM. ITM missed with OSEM had significantly lower SUVmax (mean 2.03 vs. 3.84) and TBR (mean 1.18 vs. 2.22) and higher MTV (mean 2.92 vs. 1.01) on OSEM compared to BSREM (all p < 0.001)., Conclusions: BSREM detects significantly more ITM than OSEM, owing to higher SUVmax, higher TBR, and less blurring. BSREM is particularly helpful in small and less avid lesions, which are more often missed with OSEM., Key Points: • In melanoma patients, [ 18 F]FDG PET/CT helps to detect in-transit metastases (ITM), and their detection is improved by using BSREM instead of OSEM reconstruction. • BSREM is particularly useful in small lesions., (© 2021. The Author(s).)

Lung cancer remains the leading cause of cancer-related death, and it is usually diagnosed in advanced stages (stage III or IV). Recently, the availability of targeted strategies and of immunotherapy with checkpoint inhibitors (ICI) has favorably changed patient prognosis. Treatment outcome is closely related to tumor biology and interaction with the tumor immune microenvironment (TME). While the response in molecular targeted therapies relies on the presence of specific genetic alterations in tumor cells, accurate ICI biomarkers of response are lacking, and clinical outcome likely depends on multiple factors that are both host and tumor-related. This paper is an overview of the ongoing research on predictive factors both from in vitro/ex vivo analysis (ranging from conventional pathology to molecular biology) and in vivo analysis, where molecular imaging is showing an exponential growth and use due to technological advancements and to the new bioinformatics approaches applied to image analyses that allow the recovery of specific features in specific tumor subclones.

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [ 18 F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

Objective: To identify the impact of segmentation methods and intensity discretization on radiomic features (RFs) extraction from 68 Ga-DOTA-TOC PET images in patients with neuroendocrine tumors., Methods: Forty-nine patients were retrospectively analyzed. Tumor contouring was performed manually by four different operators and with a semi-automatic edge-based segmentation (SAEB) algorithm. Three SUV max fixed thresholds (20, 30, 40%) were applied. Fifty-one RFs were extracted applying two different intensity rescale factors for gray-level discretization: one absolute (AR60 = SUV from 0 to 60) and one relative (RR = min-max of the VOI SUV). Dice similarity coefficient (DSC) was calculated to quantify segmentation agreement between different segmentation methods. The impact of segmentation and discretization on RFs was assessed by intra-class correlation coefficients (ICC) and the coefficient of variance (COV L ). The RFs' correlation with volume and SUV max was analyzed by calculating Pearson's correlation coefficients., Results: DSC mean value was 0.75 ± 0.11 (0.45-0.92) between SAEB and operators and 0.78 ± 0.09 (0.36-0.97), among the four manual segmentations. The study showed high robustness (ICC > 0.9): (a) in 64.7% of RFs for segmentation methods using AR60, improved by applying SUV max threshold of 40% (86.5%); (b) in 50.9% of RFs for different SUV max thresholds using AR60; and (c) in 37% of RFs for discretization settings using different segmentation methods. Several RFs were not correlated with volume and SUV max ., Conclusions: RFs robustness to manual segmentation resulted higher in NET 68 Ga-DOTA-TOC images compared to 18 F-FDG PET/CT images. Forty percent SUV max thresholds yield superior RFs stability among operators, however leading to a possible loss of biological information. SAEB segmentation appears to be an optimal alternative to manual segmentation, but further validations are needed. Finally, discretization settings highly impacted on RFs robustness and should always be stated.

To evaluate whether quantitative PET parameters of motion-corrected 68 Ga-DOTATATE PET/CT can differentiate between intrapancreatic accessory spleens (IPAS) and pancreatic neuroendocrine tumor (pNET). A total of 498 consecutive patients with neuroendocrine tumors (NET) who underwent 68 Ga-DOTATATE PET/CT between March 2017 and July 2019 were retrospectively analyzed. Subjects with accessory spleens (n = 43, thereof 7 IPAS) and pNET (n = 9) were included, resulting in a total of 45 scans. PET images were reconstructed using ordered-subsets expectation maximization (OSEM) and a fully convergent iterative image reconstruction algorithm with β-values of 1000 (BSREM 1000 ). A data-driven gating (DDG) technique (MOTIONFREE, GE Healthcare) was applied to extract respiratory triggers and use them for PET motion correction within both reconstructions. PET parameters among different samples were compared using non-parametric tests. Receiver operating characteristics (ROC) analyzed the ability of PET parameters to differentiate IPAS and pNETs. SUVmax was able to distinguish pNET from accessory spleens and IPAs in BSREM 1000 reconstructions (p < 0.05). This result was more reliable using DDG-based motion correction (p < 0.003) and was achieved in both OSEM and BSREM 1000 reconstructions. For differentiating accessory spleens and pNETs with specificity 100%, the ROC analysis yielded an AUC of 0.742 (sensitivity 56%)/0.765 (sensitivity 56%)/0.846 (sensitivity 62%)/0.840 (sensitivity 63%) for SUVmax 36.7/41.9/36.9/41.7 in OSEM/BSREM 1000 /OSEM + DDG/BSREM 1000  + DDG, respectively. BSREM 1000  + DDG can accurately differentiate pNET from accessory spleen. Both BSREM 1000 and DDG lead to a significant SUV increase compared to OSEM and non-motion-corrected data.

Aim: This work aims to evaluate whether the radiomic features extracted by 68Ga-DOTATOC-PET/CT of two patients are associated with the response to peptide receptor radionuclide therapy (PRRT) in patients affected by neuroendocrine tumor (NET). Methods: This is a pilot report in two NET patients who experienced a discordant response to PRRT (responder vs. non-responder) according to RECIST1.1. The patients presented with liver metastasis from the rectum and pancreas G3-NET, respectively. Whole-body total-lesion somatostatin receptor-expression (TLSREwb-50) and somatostatin receptor-expressing tumor volume (SRETV wb-50) were obtained in pre- and post-PRRT PET/CT. Radiomic analysis was performed, extracting 38 radiomic features (RFs) from the patients' lesions. The Mann-Whitney test was used to compare RFs in the responder patient vs. the non-responder patient. Pearson correlation and principal component analysis (PCA) were used to evaluate the correlation and independence of the different RFs. Results: TLSREwb-50 and SRETVwb-50 modifications correlate with RECIST1.1 response. A total of 28 RFs extracted on pre-therapy PET/CT showed significant differences between the two patients in the Mann-Whitney test ( p < 0.05). A total of seven second-order features, with poor correlation with SUVmax and PET volume, were identified by the Pearson correlation matrix. Finally, the first two PCA principal components explain 83.8% of total variance. Conclusion: TLSREwb-50 and SRETVwb-50 are parameters that might be used to predict and to assess the PET response to PRRT. RFs might have a role in defining inter-patient heterogeneity and in the prediction of therapy response. It is important to implement future studies with larger and more homogeneous patient populations to confirm the efficacy of these biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liberini, Rampado, Gallio, De Santi, Ceci, Dionisi, Thuillier, Ciuffreda, Piovesan, Fioroni, Versari, Molinari and Deandreis.)

Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a worldwide pandemic. Especially in the centers most affected by the pandemic, symptoms (such as fever, cough, myalgia, or fatigue) and/or radiological signs (such as ground-glass opacity) typically related to COVID-19 often diverted clinicians' attention from other diseases. Despite the urgency to recognize and cure SARS-CoV-2 infection, a plethora of differential diagnoses must be considered, and other diseases must be equally and promptly treated, as described in this case report., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s) 2021.)

The NETTER-1 study has proven peptide receptor radionuclide therapy (PRRT) to be one of the most effective therapeutic options for metastatic neuroendocrine tumors (NETs), improving progression-free survival and overall survival. However, PRRT response assessment is challenging and no consensus on methods and timing has yet been reached among experts in the field. This issue is owed to the suboptimal sensitivity and specificity of clinical biomarkers, limitations of morphological response criteria in slowly growing tumors and necrotic changes after therapy, a lack of standardized parameters and timing of functional imaging and the heterogeneity of PRRT protocols in the literature. The aim of this article is to review the most relevant current approaches for PRRT efficacy prediction and response assessment criteria in order to provide an overview of suitable tools for safe and efficacious PRRT.

Objectives: (1.1) to evaluate the association between baseline 18F-FDG PET/CT semi-quantitative parameters of the primary lesion with progression free survival (PFS), overall survival (OS) and response to immunotherapy, in advanced non-small cell lung carcinoma (NSCLC) patients eligible for immunotherapy; (1.2) to evaluate the application of radiomics analysis of the primary lesion to identify features predictive of response to immunotherapy; (1.3) to evaluate if tumor burden assessed by 18F-FDG PET/CT (N and M factors) is associated with PFS and OS., Materials and Methods: we retrospectively analyzed clinical records of advanced NCSLC patients (stage IIIb/c or stage IV) candidate to immunotherapy who performed 18F-FDG PET/CT before treatment to stage the disease. Fifty-seven (57) patients were included in the analysis (F:M 17:40; median age = 69 years old). Notably, 38/57 of patients had adenocarcinoma (AC), 10/57 squamous cell carcinoma (SCC) and 9/57 were not otherwise specified (NOS). Overall, 47.4% patients were stage IVA, 42.1% IVB and 8.8% IIIB. Immunotherapy was performed as front-line therapy in 42/57 patients and as second line therapy after chemotherapy platinum-based in 15/57. The median follow up after starting immunotherapy was 10 months (range: 1.5-68.6). Therapy response was assessed by RECIST 1.1 criteria (CT evaluation every 4 cycles of therapy) in 48/57 patients or when not feasible by clinical and laboratory data (fast disease progression or worsening of patient clinical condition in nine patients). Radiomics analysis was performed by applying regions of interest (ROIs) of the primary tumor delineated manually by two operators and semi-automatically applying a threshold at 40% of SUVmax., Results: (1.1) metabolic tumor volume (MTV) ( p = 0.028) and total lesion glycolysis (TLG) ( p = 0.035) were significantly associated with progressive vs. non-progressive disease status. Patients with higher values of MTV and TLG had higher probability of disease progression, compared to those patients presenting with lower values. SUVmax did not show correlation with PD status, PFS and OS. MTV ( p = 0.027) and TLG ( p = 0.022) also resulted in being significantly different among PR, SD and PD groups, while SUVmax was confirmed to not be associated with response to therapy ( p = 0.427). (1.2) We observed the association of several radiomics features with PD status. Namely, patients with high tumor volume, TLG and heterogeneity expressed by "skewness" and "kurtosis" had a higher probability of failing immunotherapy. (1.3) M status at 18F-FDG PET/CT was significantly associated with PFS ( p = 0.002) and OS ( p = 0.049). No significant associations were observed for N status., Conclusions: 18F-FDG PET/CT performed before the start of immunotherapy might be an important prognostic tool able to predict the disease progression and response to immunotherapy in patients with advanced NSCLC, since MTV, TLG and radiomics features (volume and heterogeneity) are associated with disease progression.

The 2013/59 EURATOM directive defines all nuclear medicine applications for therapeutic purpose as a form of radiotherapy and underlines the need of both justification and optimization of these procedures, including radioactive iodine therapy (RAIT) with [131I] for metastatic differentiated thyroid cancer (DTC). In metastatic DTC, optimal activity to be administered to achieve the best response rate with limited toxicity is still a matter of debate and international guidelines do not provide univocal recommendations on the preferable use of empiric versus a dosimetry-based approach in these patients. The purpose of this literature review is to describe the possible limits of dosimetry in RAIT planning according to methodological aspects, tumoral heterogeneity and to report clinical data on the impact on patients' outcome of different approaches. Due to the lack of standardized dosimetry protocols and clinical data assessing the superiority of a dosimetry-based vs an empiric approach in these patients, there is a need of standardisation and prospective, properly conducted studies to validate and to assess the best approach.

We present a rare case of a 42-year-old man with a long history of von Hippel-Lindau disease that was scanned with Ga-DOTA-TOC PET/CT for suspicion of disease relapse. Ga-DOTA-TOC imaging demonstrated increased DOTA-TOC uptake in pancreas tail and intramedullary and extramedullary spinal hemangioblastomas, only some of which have already been highlighted at MRI examination. This case illustrates the significant role the Ga-labeled somatostatin receptor analogs PET/CT in the management of the von Hippel-Lindau disease.