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Purpose: To investigate the additional value of (11)C-choline positron emission tomography (PET)-computed tomography (CT) to T2-weighted (T2w) magnetic resonance imaging (MRI) for localization of intraprostatic tumor nodules. Methods and Materials: Forty-nine prostate cancer patients underwent T2w MRI and (11)C-choline PET-CT before radical prostatectomy and extended lymphadenectomy. Tumor regions were outlined on the whole-mount histopathology sections and on the T2w MR images. Tumor localization was recorded in the basal, middle, and apical part of the prostate by means of an octant grid. To analyze (11)C-choline PET-CT images, the same grid was used to calculate the standardized uptake values (SUV) per octant, after rigid registration with the T2w MR images for anatomic reference. Results: In total, 1,176 octants were analyzed. Sensitivity, specificity, and accuracy of T2w MRI were 33.5%, 94.6%, and 70.2%, respectively. For (11)C-choline PET-CT, the mean SUV(max) of malignant octants was significantly higher than the mean SUV(max) of benign octants (3.69 ± 1.29 vs. 3.06 ± 0.97, p < 0.0001) which was also true for mean SUV(mean) values (2.39 ± 0.77 vs. 1.94 ± 0.61, p < 0.0001). A positive correlation was observed between SUV(mean) and absolute tumor volume (Spearman r = 0.3003, p = 0.0362). No correlation was found between SUVs and prostate-specific antigen, T-stage or Gleason score. The highest accuracy (61.1%) was obtained with a SUV(max) cutoff of 2.70, resulting in a sensitivity of 77.4% and a specificity of 44.9%. When both modalities were combined (PET-CT or MRI positive), sensitivity levels increased as a function of SUV(max) but at the cost of specificity. When only considering suspect octants on (11)C-choline PET-CT (SUV(max) ≥ 2.70) and T2w MRI, 84.7% of these segments were in agreement with the gold standard, compared with 80.5% for T2w MRI alone. Conclusions: The additional value of (11)C-choline PET-CT next to T2w MRI in detecting tumor nodules within the prostate is limited. [ABSTRACT FROM AUTHOR]

We provide updated guidance and standards for the indication, acquisition, and interpretation of [ 18 F]FDG PET/CT for plasma cell disorders. Procedures and characteristics are reported and different scenarios for the clinical use of [ 18 F]FDG PET/CT are discussed. This document provides clinicians and technicians with the best available evidence to support the implementation of [ 18 F]FDG PET/CT imaging in routine practice and future research., (© 2024. The Author(s).)

[ 18 F]AlF-NOTA-octreotide ([ 18 F]AlF-OC) is a promising alternative for [ 68 Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [ 18 F]AlF-OC PET/CT and [ 68 Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [ 18 F]AlF-OC and [ 68 Ga]Ga-DOTA-TATE or [ 68 Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [ 68 Ga]Ga-DOTA-SSA or [ 18 F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [ 18 F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [ 68 Ga]Ga-DOTA-SSA, the use of [ 18 F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [ 18 F]AlF-OC. The use of [ 18 F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [ 18 F]AlF-OC PET/CT as an alternative for [ 68 Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15., (© 2024 British Society for Neuroendocrinology.)

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours., (© 2024 British Society for Neuroendocrinology.)

Purpose: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands., Methods: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO)., Results: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma., Conclusion: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations., (© 2024. The Author(s).)

Background: The C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in many cancers, e.g. multiple myeloma and acute leukemia, yet solely [ 68 Ga]PentixaFor is used for clinical PET imaging. The aim of this study was to develop and assess a second generation Al 18 F-labeled D-amino acid peptide based on the viral macrophage inflammatory protein II for CXCR4 targeted molecular imaging., Methods: We designed a library of monomer and multimer constructs and evaluated their binding affinity for human and mouse CXCR4. Based on these results, we selected the best vector molecule for development of an Al 18 F-labeled ligand, [ 18 F]AlF-NOTA-2xDV1(c11sc12s), which was further evaluated in a cell-based binding assay to assess its binding properties and specificity for CXCR4. Next, pharmacokinetics and tumor uptake of [ 18 F]AlF-NOTA-2xDV1(c11sc12s) were evaluated in naïve mice and mice with xenografts derived from U87.CXCR4 cells. Finally, we performed an imaging study in a non-human primate to assess the in vivo distribution of this novel radioligand in a species closely related to humans., Results: The lead ligand AlF-NOTA-2xDV1(c11sc12s) showed six-fold higher affinity for human CXCR4 compared to Ga-Pentixafor. The corresponding radiotracer was obtained in a good radiochemical yield of 40.1 ± 13.5 % (n = 4) and apparent molar activity of 20.4 ± 3.3 MBq/nmol (n = 4) after optimization. In U87.CD4.CXCR4 cell binding assays, the total bound fraction of [ 18 F]AlF-NOTA-(2×)DV1(c11sc12s) was 32.4 ± 1.8 %. This fraction could be reduced by 82.5 % in the presence of 75 μM AMD3100. In naïve mice, [ 18 F]AlF-NOTA-2xDV1(c11sc12s) accumulated in organs expressing mouse CXCR4, e.g. the liver (SUV mean (mean standardized uptake value) 75 min p.i. 11.7 ± 0.6), which was blockable by co-injecting AMD3100 (5 mg/kg). In U87.CXCR4 xenografted tumor mice, the tumor uptake of [ 18 F]AlF-NOTA-2xDV1(c11sc12s) remained low (SUV mean 0.5 ± 0.1), but was reduced by co-administration of AMD3100. Surprisingly, [ 18 F]AlF-NOTA-2xDV1(c11sc12s) exhibited a similar biodistribution in a non-human primate as in mice indicating off-target binding of [ 18 F]AlF-NOTA-2xDV1(c11sc12s) in liver tissue. We confirmed that [ 18 F]AlF-NOTA-2xDV1(c11sc12s) is taken up by hepatocytes using in vitro studies and that the uptake can be blocked with AMD3100 and rifampicin, a potent organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 inhibitor., Conclusion: The second generation D-peptide AlF-NOTA-2xDV1(c11sc12s) showed high affinity for human CXCR4 and the corresponding radiotracer was produced in good radiochemical yields. However, [ 18 F]AlF-NOTA-2xDV1(c11sc12s) is not specific for CXCR4 and is also a substrate for OATP1B1 and/or OATP1B3, known to mediate hepatic uptake. Therefore, D-amino acid peptides, based on the viral macrophage inflammatory protein II, are not the prefered vector molecule for the development of CXCR4 targeting molecular imaging tools., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Terbium features four clinically interesting radionuclides for application in nuclear medicine: terbium-149, terbium-152, terbium-155, and terbium-161. Their identical chemical properties enable the synthesis of radiopharmaceuticals with the same pharmacokinetic character, while their distinctive decay characteristics make them valuable for both imaging and therapeutic applications. In particular, terbium-152 and terbium-155 are useful candidates for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, respectively; whereas terbium-149 and terbium-161 find application in α- and β - -/Auger electron therapy, respectively. This unique characteristic makes the terbium family ideal for the "matched-pair" principle of theranostics. In this review, the advantages and challenges of terbium-based radiopharmaceuticals are discussed, covering the entire chain from radionuclide production to bedside administration. It elaborates on the fundamental properties of terbium, the production routes of the four interesting radionuclides and gives an overview of the available bifunctional chelators. Finally, we discuss the preclinical and clinical studies as well as the prospects of this promising development in nuclear medicine., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research., (© 2023 British Society for Neuroendocrinology.)

Background: Somatostatin receptor (SSTR) positron emission tomography (PET) is a cornerstone of neuroendocrine tumor (NET) management. Hybrid PET/magnetic resonance imaging (MRI) is now available for NET-imaging, next to PET/computed tomography (CT)., Objectives: To determine whether CT or MRI is the best hybrid partner for [ 68 Ga]Ga-DOTATATE PET., Design: Monocentric, prospective study., Methods: Patients received a same-day [ 68 Ga]Ga-DOTATATE PET/CT and subsequent PET/MRI, for suspicion of NET, (re)staging or peptide receptor radionuclide therapy-selection. The union (PET union ) of malignant lesions detected on PET CT and PET MRI was the reference standard. Concordance of detection of malignant lesions in an organ was measured between PET union and CT and PET union and MRI. Seven bins were used to categorize the number of malignant lesions, containing following ordinal variables: 0, 1, 2-5, 6-10, 11-20, >20 countable and diffuse/uncountable. The difference in number of malignant lesions was obtained as the difference in bin level ('Δbin') between PET union and CT and PET union and MRI with a Δbin closer to zero implying a higher concordance rate., Results: Twenty-nine patients were included. Primary tumors included 17 gastroenteropancreatic-NETs, 1 colon neuroendocrine carcinoma, 7 lung-NETs and 2 meningiomas. Patient level concordance with PET union was 96% for MRI and 67% for CT ( p = 0.039). Organ level concordance with PET union was 74% for MRI and 40% for CT ( p < 0.0001). In bone, there was a higher concordance rate for MRI compared to CT, 92% and 33%, respectively ( p = 0.016). Overall, a mean Δbin of 0.5 ± 1.1 for PET union /MRI and 1.4 ± 1.2 for PET union /CT ( p < 0.0001) was noted. In liver, a mean Δbin of 0.0 ± 1.1 for PET union /MRI and 1.7 ± 1.2 for PET union /CT was observed ( p = 0.0078). In bone, a mean Δbin closer to zero was observed for PET union /MRI compared to PET union /CT, 0.6 ± 1.4 and 2.0 ± 1.5, respectively ( p = 0.0098)., Conclusions: Compared to SSTR PET/CT, SSTR PET/MRI had a higher patient and organ level concordance for malignant tumoral involvement and number of malignant lesions, with a clear added value in bone and liver specifically., Competing Interests: No conflicts of interest relevant to this work exist. CMD has been a consultant for Terumo, Ipsen, Sirtex, Bayer and PSI CRO. KVL has received speaker fees from GE Healthcare., (© The Author(s), 2023.)

Purpose: The aim of this joint EANM/SNMMI/IHPBA procedure guideline is to provide general information and specific recommendations and considerations on the use of [ 99m Tc]Tc-mebrofenin hepatobiliary scintigraphy (HBS) in the quantitative assessment and risk analysis before surgical intervention, selective internal radiation therapy (SIRT) or before and after liver regenerative procedures. Although the gold standard to estimate future liver remnant (FLR) function remains volumetry, the increasing interest in HBS and the continuous request for implementation in major liver centers worldwide, demands standardization., Methods: This guideline concentrates on the endorsement of a standardized protocol for HBS elaborates on the clinical indications and implications, considerations, clinical appliance, cut-off values, interactions, acquisition, post-processing analysis and interpretation. Referral to the practical guidelines for additional post-processing manual instructions is provided., Conclusion: The increasing interest of major liver centers worldwide in HBS requires guidance for implementation. Standardization facilitates applicability of HBS and promotes global implementation. Inclusion of HBS in standard care is not meant as substitute for volumetry, but rather to complement risk evaluation by identifying suspected and unsuspected high-risk patients prone to develop post-hepatectomy liver failure (PHLF) and post-SIRT liver failure., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Malignancy-associated cerebellar hypermetabolism on [ 18 F]FDG PET/CT has 2 major causes: paraneoplastic autoimmune encephalitis and neoplasias (leptomeningeal/cerebellar metastases and primary cerebellar tumors). We present the case of a 33-year-old man with a newly diagnosed Hodgkin lymphoma and mere episodical headache, unexpectedly displaying intense cerebellar hypermetabolism on his staging [ 18 F]FDG PET/CT. Both neurolymphomatosis and paraneoplastic subacute cerebellar degeneration were ruled out by clinical presentation, MR, and repeated lumbar punctures. Instead, cerebrospinal fluid analysis unveiled a Cryptococcus neoformans meningitis, highlighting the possibility of paucisymptomatic central nervous system infections as differential diagnosis in malignancy-related cerebellar hypermetabolism in addition to (para)neoplastic causes., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Fluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [ 18 F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [ 18 F]AlF-OC PET/CT outperforms [ 68 Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [ 18 F]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [ 18 F]AlF-OC ("incremental lesions")., Methods: Ten patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [ 68 Ga]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [ 18 F]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient., Results: In total, 195 unique lesions were detected: 167 with [ 68 Ga]Ga-DOTATATE and 193 with [ 18 F]AlF-OC. The DR for [ 18 F]AlF-OC was 99.1% versus 91.4% for [ 68 Ga]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [ 18 F]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [ 18 F]AlF-OC, of which 91% were confirmed by MRI and considered true positives., Conclusion: The DR of [ 18 F]AlF-OC was numerically higher and non-inferior to the DR of [ 68 Ga]Ga-DOTATATE. [ 18 F]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [ 18 F]AlF-OC as a new alternative for SSTR PET in clinical practice. Trial registration ClinicalTrials.gov: NCT04552847. Registered 17 September 2020, https://beta., Clinicaltrials: gov/study/NCT04552847., (© 2023. The Author(s).)

Molecular imaging of the somatostatin receptor plays a key role in the clinical management of neuroendocrine tumors. PET imaging with somatostatin analogs (SSAs) labeled with 68 Ga or 64 Cu is currently the gold standard in clinical practice. However, widespread implementation of 68 Ga imaging is often hampered by practical and economic issues related to 68 Ge/ 68 Ga generators. 18 F offers several advantages to tackle these issues. Recent developments in radiochemistry have allowed a shift from 68 Ga toward 18 F labeling, leading to promising clinical translations of 18 F-labeled SSAs, such as Gluc-Lys-[ 18 F]FP-TOCA, [ 18 F]F-FET-βAG-TOCA, [ 18 F]AlF-NOTA-octreotide, [ 18 F]SiTATE, and [ 18 F]AlF-NOTA-JR11. This review gives an update of currently available clinical data regarding 18 F-labeled SSA tracers and provides justification for the clinical application of this class of tracers., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Aim: To build and externally validate an [ 18 F]FDG PET radiomic model to predict overall survival in patients with head and neck squamous cell carcinoma (HNSCC)., Methods: Two multicentre datasets of patients with operable HNSCC treated with preoperative afatinib who underwent a baseline and evaluation [ 18 F]FDG PET/CT scan were included (EORTC: n = 20, Unicancer: n = 34). Tumours were delineated, and radiomic features were extracted. Each cohort served once as a training and once as an external validation set for the prediction of overall survival. Supervised feature selection was performed using variable hunting with variable importance, selecting the top two features. A Cox proportional hazards regression model using selected radiomic features and clinical characteristics was fitted on the training dataset and validated in the external validation set. Model performances are expressed by the concordance index (C-index)., Results: In both models, the radiomic model surpassed the clinical model with validation C-indices of 0.69 and 0.79 vs. 0.60 and 0.67, respectively. The model that combined the radiomic features and clinical variables performed best, with validation C-indices of 0.71 and 0.82., Conclusion: Although assessed in two small but independent cohorts, an [ 18 F]FDG-PET radiomic signature based on the evaluation scan seems promising for the prediction of overall survival for HNSSC treated with preoperative afatinib. The robustness and clinical applicability of this radiomic signature should be assessed in a larger cohort.

Background: Uveal melanoma is an orphan malignancy with very limited data on treatment options in metastatic setting., Methods: In this single - center retrospective study, we describe real-world epidemiological and survival data on 121 metastatic uveal melanoma (MUM) patients registered in our institution. As a large tertiary referral center, almost 30% of all diagnoses in the Flemish region of Belgium were covered. Primarily, we determined whether introduction of immune checkpoint inhibitors (ICI) led to improved overall survival (OS) in MUM patients. Secondarily, response rates to ICI were assessed and we evaluated whether first-line ICI could be a valid alternative to liver-directed therapy (LDT) in liver-only disease., Results: The initially perceived 10.8 months survival benefit from treatment with ICI disappeared after correction for immortality bias. By analyzing treatment type as time-varying covariate on OS, no significant benefit of ICI over other systemic therapies (HR = 0.771) or best supportive care (BSC) (HR = 0.780) was found. Also comparison of the pre-ICI versus ICI era showed no OS improvement after introduction of ICI in our center ( p  = 0.7994). Only liver-directed and local oligometastatic approaches were associated with a lower chance of mortality when compared to ICI ( p  = 0.0025), other systemic therapies ( p  = 0.0001) and BSC ( p  = 0.0003), yet without correction for selection bias. We reported overall response rates on ICI ranging from 8-15% and we found some support for neoadjuvant strategies with ICI resulting in remission or downsizing, allowing oligometastatic approaches later on. In first-line liver-only disease, median real-world progression-free survival and OS did not significantly differ between patients treated with LDT or ICI upfront ( p  = 0.2930 and p  = 0.5461 respectively)., Conclusion: Although we documented responses to ICI, our analyses do not demonstrate an OS benefit of ICI over alternative treatment strategies for MUM. However, local treatment options, whether liver-directed or for oligometastatic disease, may be beneficial and should be considered.

18 F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68 Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, 18 F-AlF-NOTA-octreotide ( 18 F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68 Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18 F-AlF-OC compared with 68 Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68 Ga-DOTATATE ( n = 56) or 68 Ga-DOTANOC ( n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18 F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18 F-AlF-OC and 68 Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUV max and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68 Ga-DOTATATE/NOC and 4,278 with 18 F-AlF-OC. The mean DR with 18 F-AlF-OC was significantly higher than with 68 Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10 -5 ). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68 Ga-DOTATATE and 68 Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUV max were observed ( P = 0.067), but mean tumor-to-background ratio was significantly higher with 18 F-AlF-OC than with 68 Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18 F-AlF-OC is noninferior and even superior to 68 Ga-DOTATATE/NOC PET in NET patients. This validates 18 F-AlF-OC as an option for clinical practice somatostatin receptor PET., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: [ 18 F]AlF-NOTA-octreotide is an 18 F-labeled somatostatin analogue which is a good clinical alternative for 68 Ga-labeled somatostatin analogues. However, radiolabeled somatostatin receptor (SSTR) antagonists might outperform agonists regarding imaging sensitivity of neuroendocrine tumors (NETs). No direct comparison between the antagonist [ 18 F]AlF-NOTA-JR11 and the agonist [ 18 F]AlF-NOTA-octreotide as SSTR PET probes is available. Herein, we present the radiosynthesis of [ 18 F]AlF-NOTA-JR11 and compare its NETs imaging properties directly with the established agonist radioligand [ 18 F]AlF-NOTA-octreotide preclinically., Methods: [ 18 F]AlF-NOTA-JR11 was synthesized in an automated synthesis module. The in vitro binding characteristics (IC 50 ) of [ nat F]AlF-NOTA-JR11 and [ nat F]AlF-NOTA-octreotide were evaluated and the in vitro stability of [ 18 F]AlF-NOTA-JR11 was determined in human serum. In vitro cell binding and internalization was performed with [ 18 F]AlF-NOTA-JR11 and [ 18 F]AlF-NOTA-octreotide using SSTR2 expressing cells and the pharmacokinetics were evaluated using μPET/CT in mice bearing BON1.SSTR2 tumor xenografts., Results: Excellent binding affinity for SSTR2 was found for [ nat F]AlF-NOTA-octreotide (IC 50 of 25.7 ± 7.9 nM). However, the IC 50 value for [ nat F]AlF-NOTA-JR11 (290.6 ± 71 nM) was 11-fold higher compared to [ nat F]AlF-NOTA-octreotide, indicating lower affinity for SSTR2. [ 18 F]AlF-NOTA-JR11 was obtained in a good RCY (50 ± 6 %) but with moderate RCP of 94 ± 1 %. [ 18 F]AlF-NOTA-JR11 demonstrated excellent stability in human serum (>95 % after 240 min). 2.7-fold higher cell binding was observed for [ 18 F]AlF-NOTA-JR11 as compared to [ 18 F]AlF-NOTA-octreotide after 60 min. μPET/CT images demonstrated comparable pharmacokinetics and tumor uptake between [ 18 F]AlF-NOTA-JR11 (SUV max : 3.7 ± 0.8) and [ 18 F]AlF-NOTA-octreotide (SUV max : 3.6 ± 0.4)., Conclusions: [ 18 F]AlF-NOTA-JR11 was obtained in good RCY, albeit with a moderate RCP. The cell binding study showed significant higher binding of [ 18 F]AlF-NOTA-JR11 compared to [ 18 F]AlF-NOTA-octreotide, despite the higher IC 50 value of AlF-NOTA-JR11. However, pharmacokinetics and in vivo tumor uptake was comparable for both radiotracers. Novel Al 18 F-labeled derivatives of JR11 with higher SSTR2 affinity should be developed for increased tumor uptake and NET imaging sensitivity., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2023 KU leuven. Published by Elsevier Inc. All rights reserved.)

Purpose: Despite its limitations, [ 123 I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [ 18 F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [ 18 F]MFBG and perform a head-to-head comparison with [ 123 I]MIBG in neural crest tumour patients., Methods: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [ 123 I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [ 18 F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [ 18 F]MFBG. Normal organ uptake (SUV mean ) and lesion uptake (SUV max ; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (V T ) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [ 18 F]MFBG and [ 123 I]MIBG., Results: [ 18 F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [ 123 I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median V T was 37.4 mL/cm 3 (range: 18.0-144.8) with an excellent correlation between V T and SUV mean at all 3 time points (R 2 : 0.92-0.94). Mean lesion SUV max and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [ 123 I]MIBG were also observed with [ 18 F]MFBG. The mean DR with [ 123 I]MIBG was significantly lower than with [ 18 F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043)., Conclusion: [ 18 F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [ 123 I]MIBG scintigraphy., Trial Registration: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Knowledge regarding the gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass is urgently needed to understand, prevent and treat the nutritional and pharmacological complications of bariatric surgery., Aim: To investigate the effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal motility (e.g., transit and pressure), pH, and intestinal bile acid concentration., Material and Methods: An exploratory cross-sectional study was performed in six participants living with obesity, six participants who underwent sleeve gastrectomy, and six participants who underwent Roux-en-Y gastric bypass. During the first visit, a wireless motility capsule (SmartPill©) was ingested after an overnight fast to measure gastrointestinal transit, pH, and pressure. During the second visit, a gastric emptying scintigraphy test of a nutritional drink labeled with 99m Tc-colloid by a dual-head SPECT gamma camera was performed to measure gastric emptying half-time (GET 1/2 ). During the third visit, two customized multiple lumen aspiration catheters were positioned to collect fasting and postprandial intestinal fluids to measure bile acid concentration., Results: Immediate pouch emptying (P = 0.0007) and a trend for faster GET 1/2 (P = 0.09) were observed in both bariatric groups. There was a tendency for a shorter orocecal transit in participants with sleeve gastrectomy and Roux-en-Y gastric bypass (P = 0.08). The orocecal segment was characterized by a higher 25th percentile pH (P = 0.004) and a trend for a higher median pH in both bariatric groups (P = 0.07). Fasting total bile acid concentration was 7.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) and 3.5-fold higher in the jejunum after sleeve gastrectomy (P = 0.009) compared to obesity. Postprandial bile acid concentration was 3-fold higher in the jejunum after sleeve gastrectomy (P = 0.0004) and 6.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) compared to obesity., Conclusion: The anatomical alterations of sleeve gastrectomy and Roux-en-Y gastric bypass have an important impact on gastrointestinal physiology. This data confirms changes in transit and pH and provides the first evidence for altered intraluminal bile acid concentration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Several studies have shown a strong predictive value for pretreatment [ 18 F]FDG-PET/CT metabolic parameters in different lymphoma subtypes. However, few publications exist concerning the role of metabolic parameters in mantle cell lymphoma (MCL). We retrospectively investigated the prognostic value of baseline metabolic tumor volume (MTV) and lesion dissemination in untreated MCL. We compared it to currently used prognostic factors such as stage, mantle cell lymphoma international prognostic index (MIPI) and KI-67. We report that a higher baseline MTV is a risk factor for worse overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) in univariate analysis. In multivariate analysis, MTV was significantly associated with DSS, but not with OS and PFS. We found no correlation between lesion dissemination and outcome. The MIPI score remains the strongest predictor of outcome. These results show that MTV is an important prognostic tool and can improve patient risk stratification at staging of untreated MCL.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL., Competing Interests: VV reports consultancy fees from Beigene, BMS/Cellgene, Gilead/Kite, speaker fees from from Janssen, travel support from Amgen, Abbvie; all paid to her institution. CMD reports consultancy fees from Sirtex, PSI CRO, Terumo and Ipsen and speaker fees from Ipsen; all paid to his institution. WL reports consultancy fees from Boston-Scientific, Cook Medical, CLS Behring, Echosens, Evive Biotech, Genfit, Norgine, Abbvie, Gore and Intercept.; all paid to institution. TT reports consultancy and speaker fees from EUSApharma; all paid to his institution. TT holds a Mandate for Fundamental and Translational Research from the ‘Stichting tegen Kanker’ (2014-083 and 2019-091). DD reports grants/research support from Roche; personal fees/honoraria from Takeda, Novartis, Amgen, Atara Biotherapeutics, Incyte; all paid to his institution. DD holds a mandate for Clinical and Translational Research from “Kom op tegen Kanker” (2017/10908/2816). RV is a senior clinical research fellow of the Research Foundation Flanders (FWO). BS is a senior clinical investigator of the Research Foundation Flanders (1842919N) and received funding from the Foundation Against Cancer (Stichting tegen Kanker; C/2020/1380). The remaining 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 © 2022 Vergote, Deroose, Fieuws, Laleman, Sprangers, Uyttebroeck, Van Cleemput, Verhoef, Vos, Tousseyn and Dierickx.)

Background: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol heterogeneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points., Patients and Methods: Acknowledging the recently highlighted potential of radiomics and artificial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method., Results: Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified., Conclusion: This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these imaging standards across recruiting centres., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.H. reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from Y-mAbs, all outside the submitted work. L.B. is a cofounder of Collective Minds Radiology. R.C. reports travel support by Bracco Imaging. T.D. reports honorary fees and travel support by Siemens, Canon, Bayer, b.e. imaging and research grants by Siemens Healthineers, Bayer, Guerbet and b.e. imaging. E.L. reports receiving research grants from AIRC and from the Italian Ministry of Health, and faculty remuneration from ESMIT (European School of Multimodality Imaging and Therapy) and MI&T Congressi. D.E.O.-L. received expert remuneration from EAU for participating in PET PSMA Consensus Meeting in January 2022. The remaining authors declare that they have no conflict of interest related to this study. W.G.K. reports personal fees from Bristol-Myers Squibb., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To meet the increasing demand for PRRT in the treatment of patients with inoperable/disseminated well-differentiated neuroendocrine tumors (NETs) and to guide optimization strategies, adequate and accessible predictive tools that allow to stratify patients who will benefit from treatment from those who will not are becoming indispensable. Previously, we have investigated the role of baseline [ 68 Ga]Ga-DOTATOC PET tumor uptake and volumetric parameters and a blood-derived inflammatory biomarker, the inflammation-based index (IBI), for outcome prediction in NET patients treated with [ 90 Y]Y-DOTATOC. In this retrospective study in 83 NET patients treated with [ 177 Lu]Lu-DOTATATE in a routine clinical setting, we aimed to evaluate the generalizability of our previous findings to [ 177 Lu]Lu-DOTATATE treatment combined with a pre-therapeutic [ 68 Ga]Ga-DOTATATE PET. A semi-automatic customized SUV threshold-based approach was used for tumor delineation. The previously identified SUV mean cut-off of 13.7 for better survival could not be applied to this patient cohort. Instead, a more optimal cut-off could be identified: an SUV mean lower or equal than 11.2 was associated with worse overall survival (OS) (hazard ratio (HR) 2.28; P = 0.008). Also in line with our previous study, a [ 68 Ga]Ga-DOTATATE-avid tumor volume (TV) higher than 672 mL and an elevated baseline IBI were correlated with worse OS (HR 3.13 (P = 0.0001) and HR 2.00 (P = 0.034), respectively). Multivariate analysis confirmed independent associations between OS and baseline IBI (P = 0.032), SUV mean (P = 0.027) and [ 68 Ga]Ga-DOTATATE-avid TV (P = 0.001). Taking baseline IBI, [ 68 Ga]Ga-DOTATATE-avid TV and [ 68 Ga]Ga-DOTATATE uptake into account may help guide PRRT treatment decisions., Competing Interests: Chris Verslype has received research grants and performed consultancy services for Novartis, Ipsen and Bayer outside the submitted work. Paul M Clement has received study budget funds from AstraZeneca and was advisory board member for AbbVie, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Leo Pharma, Merck Serono, MSD, Rakuten, Takeda, and Vifor Pharma outside the submitted work. Eric Van Cutsem has received research grants and personal fees for consultancy from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche and Servier outside the submitted work. Christophe M Deroose has been a consultant for Terumo, Ipsen, Sirtex, Bayer and PSI CRO outside the scope of the submitted work. There are no other conflicts of interest., (AJNMMI Copyright © 2022.)

Background: Lesion/tissue segmentation on digital medical images enables biomarker extraction, image-guided therapy delivery, treatment response measurement, and training/validation for developing artificial intelligence algorithms and workflows. To ensure data reproducibility, criteria for standardised segmentation are critical but currently unavailable., Methods: A modified Delphi process initiated by the European Imaging Biomarker Alliance (EIBALL) of the European Society of Radiology (ESR) and the European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group was undertaken. Three multidisciplinary task forces addressed modality and image acquisition, segmentation methodology itself, and standards and logistics. Devised survey questions were fed via a facilitator to expert participants. The 58 respondents to Round 1 were invited to participate in Rounds 2-4. Subsequent rounds were informed by responses of previous rounds., Results/conclusions: Items with ≥ 75% consensus are considered a recommendation. These include system performance certification, thresholds for image signal-to-noise, contrast-to-noise and tumour-to-background ratios, spatial resolution, and artefact levels. Direct, iterative, and machine or deep learning reconstruction methods, use of a mixture of CE marked and verified research tools were agreed and use of specified reference standards and validation processes considered essential. Operator training and refreshment were considered mandatory for clinical trials and clinical research. Items with a 60-74% agreement require reporting (site-specific accreditation for clinical research, minimal pixel number within lesion segmented, use of post-reconstruction algorithms, operator training refreshment for clinical practice). Items with ≤ 60% agreement are outside current recommendations for segmentation (frequency of system performance tests, use of only CE-marked tools, board certification of operators, frequency of operator refresher training). Recommendations by anatomical area are also specified., (© 2022. The Author(s).)

Objectives: For the detection of bone marrow (BM) metastases in patients with neuroblastoma, microscopic BM examination and [ 123 I]MIBG scintigraphy are advised. The aims of this study were to assess the concordance of [ 123 I]MIBG and microscopic BM examination (aspirate and biopsy) in detecting BM involvement and to compare invasive disease in BM biopsies and aspirates, both at diagnosis and before autologous stem cell collection (ASCC)., Methods: Fifty-five patients with stage 4 or stage 4S disease were included, and 37 of them received an autologous hematopoietic stem cell transplantation (AHSCT). The concordance rate was measured and paired binary data were analysed by the McNemar test to look for a systematic difference between diagnostic tests., Results: At diagnosis and before ASCC, we found acceptable concordance rates for [ 123 I]MIBG versus microscopic BM examination (77.1% and 85.3% respectively). Discordant results were found in both directions and at both time points. The concordance rate for biopsy versus aspirate at diagnosis was 80.6%, however, before ASCC a much higher concordance rate between both microscopic examinations was found (94.1%). While none of the aspirates showed neuroblastoma cells before ASCC, two biopsies still showed tumor invasion., Conclusion: For patients with neuroblastoma, a [ 123 I]MIBG scintigraphy and a microscopic examination of BM aspirate and its biopsy should be used as complementary tools in the evaluation of BM involvement, and this both at diagnosis and during treatment (before ASCC).

Background : Radiolabeled somatostatin analogues ( e.g. [ 68 Ga]Ga-DOTATATE and [ 177 Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [ 18 F]AlF-NOTA-octreotide, a promising 18 F-labeled somatostatin analogue and potential alternative for 68 Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar ( e.g. Al 18 F-method in combination with therapeutic radiometals 213 Bi/ 177 Lu) or identical ( e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients. In this study we evaluated 3p- C -NETA, as potential theranostic Al 18 F-chelator and present first results of radiosynthesis and preclinical evaluation of [ 18 F]AlF-3p- C -NETA-TATE. Methods : 3p- C -NETA was synthesized and radiolabeled with diagnostic ( 68 Ga, Al 18 F) or therapeutic ( 177 Lu, 161 Tb, 213 Bi, 225 Ac and 67 Cu) radionuclides at different temperatures (25-95 °C). The in vitro stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum. 3p- C -NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis. [ 18 F]AlF-3p- C -NETA-TATE was synthesized in an automated AllinOne® synthesis module and the in vitro stability of [ 18 F]AlF-3p- C -NETA-TATE was evaluated in formulation buffer, PBS and human serum. [ 18 F]AlF-3p- C -NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [ 18 F]AlF-NOTA-Octreotide as benchmark. Results : 3p- C -NETA quantitatively sequestered 177 Lu, 213 Bi and 67 Cu at 25 °C while heating was required to bind Al 18 F, 68 Ga, 161 Tb and 225 Ac efficiently. The [ 18 F]AlF-, [ 177 Lu]Lu- and [ 161 Tb]Tb-3p- C -NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period. In contrast, [ 67 Cu]Cu- and [ 225 Ac]Ac-, [ 68 Ga]Ga-3p- C -NETA were stable in PBS, but not in human serum. [ 18 F]AlF-3p- C -NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [ 18 F]AlF-3p- C -NETA-TATE displayed good in vitro stability for 4 h in all tested conditions. Finally, [ 18 F]AlF-3p- C -NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [ 18 F]AlF-NOTA-Octreotide. Conclusions : 3p- C -NETA is a versatile chelator that can be used for both diagnostic applications (Al 18 F) and targeted radionuclide therapy ( 213 Bi, 177 Lu, 161 Tb). It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To report on organ preservation following chemoradiotherapy (CRT) in a prospective cohort of locally advanced rectal cancer patients., Methods and Materials: Fifty-two patients received CRT. MRI and 18 F-FDG-PET/CT were performed prior to CRT. Response assessment was done 6 and 12 weeks after CRT using digital rectal examination, MRI, 18 F-FDG-PET/CT and endoscopy. For clinical complete response or minimal residual disease, a watch-and-wait (W&W) protocol was started.Regrowth-free survival (ReFS), Total Mesorectal Excision-free disease-free survival, distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier method. Functional outcome was compared with the Wilcoxon signed-rank test using EORTC QLQ-C30, MSKCC BFI, LARS and IIEF-5/FSFI-5 questionnaires. A previously developed prediction model performance was tested using receiver operating characteristic analysis., Results: 29/52 patients entered a W&W protocol. There was no difference in two-year DMFS (81.1 % vs 78.8 %, p = 0.82), two-year OS (96.4 % vs 100 %, p = 0.38) and two-year DFS (77.5 % vs 78.8 %, p = 0.87) between W&W patients and those who underwent surgery at 12 weeks after CRT. Two-year DMFS differed between W&W with local regrowth, W&W with sustained response and patients who had surgery (66.7 % vs 88.0 % vs 78.8 %; p = 0.04). At 6 and 12 months, W&W patients reported good QoL and bowel function. The model validation reached an AUC of 0.627., Conclusion: Good functional outcome in patients with rectal cancer allocated to surveillance after CRT needs to be balanced against potentially worse DMFS in a subset of patients without sustained clinical complete response. Reliable prediction of patients eligible for surveillance programs needs further investigation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours (PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with [ 18 F]FDG PET/CT in a subgroup of patients., Methods: SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available, [ 18 F]FDG PET/CT images were also evaluated. The maximum standardized uptake (SUV max ) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUV max values were related to the tumour type (TC versus AC) for both SSTR and [ 18 F]FDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUV max values were compared to the pathological status (N + versus N - ) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed., Results: A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed. [ 18 F]FDG PET/CT was available in 46 patients. Analysis of the SUV max values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUV max 18.4 vs 3.8; p = 0.003) and significantly higher [ 18 F]FDG uptake in AC compared to TC (median SUV max 5.4 vs 3.5; p = 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on [ 18 F]FDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/[ 18 F]FDG SUV max values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for [ 18 F]FDG PET/CT (difference 0.17; 95% confidence interval - 0.03 to 0.38; p = 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed., Conclusion: Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for [ 18 F]FDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines., (© 2022. The Author(s).)

Purpose To evaluate the predictive value of 7-week apparent diffusion coefficient change from baseline (ADCratio 7w ) at whole-body diffusion-weighted MRI (WB-DWI MRI) after one peptide receptor radionuclide therapy (PRRT) cycle to predict outcome in patients with metastatic neuroendocrine tumor (mNET). Materials and Methods From April 2009 to May 2012, participants in a prospective clinical trial investigating yttrium 90-DOTA Phe1-Tyr 3 -octreotide (DOTATOC) treatment for mNET (EudraCT no. 2008-007965-22) underwent WB-DWI MRI and gallium 68 ( 68 Ga)-DOTATOC PET/CT before and 7 weeks after one PRRT cycle. ADCratio 7w response was compared with the 7-week Response Evaluation Criteria in Solid Tumors version 1.1 and 68 Ga-DOTATOC PET/CT quantitative responses to predict overall survival (OS) and progression-free survival (PFS) with Cox regression analysis. Results Forty participants were analyzed (mean age, 60 years ± 11 [SD]; 21 men). Median PFS and OS were 10.5 months (range, 2-36 months) and 18 months (range, 3-81 months), respectively. Survival analysis showed significantly positive effects on PFS by age (hazard ratio [HR] = 0.96, P = .007), tumor grade (HR = 2.84, P = .006), Ki-67 index (HR = 1.05, P = .01), ADCratio 7w of the least-responding lesion (ADCratio 7w-least ) (HR = 0.94, P < .001), and baseline mean standardized uptake values (SUV mean ) (HR = 0.89, P = .02), with ADCratio 7w-least and SUV mean remaining significant in multivariable analysis ( P < .001, P = .02, respectively). There were significantly positive effects on OS by pretreatment lesion volume (HR = 1.004, P = .004), tumor grade (HR = 2.14, P = .04), Ki-67 index (HR = 1.05, P = .01), and ADCratio 7w-least (HR = 0.97, P < .001), with pretreatment volume and ADCratio 7w-least remaining significant at multivariable analysis ( P = .005, P = .002, respectively). Conclusion The ADCratio 7w after start of PRRT for mNET was an independent predictor of patient outcome. Keywords: MR-Diffusion-Weighted Imaging, Radionuclide Therapy, Whole-Body Imaging, Metastases, Tumor Response, Treatment Effects EudraCT no. 2008-007965-22 © RSNA, 2022.

Abstract: Two women were referred for an 18F-PSMA-1007 PET/CT in follow-up of an adenoid cystic tumor of the subglottic region and the bronchus, respectively. Only limited tracer uptake was seen in the region of local recurrence and in the region of known metastases. Unexpectedly, an incidental finding consisting of a high tracer uptake at a corpus luteum in the ovary was found in both women., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The European Neuroendocrine Tumor Society (ENETS) promotes practices and procedures that aim to improve the standard of care delivered to patients diagnosed with or suspected of having neuroendocrine neoplasia (NEN). At its annual Scientific Advisory Board Meeting in 2018, experts in imaging, pathology and clinical care of patients with NEN drafted guidance for the standardised reporting of diagnostic studies critical to the diagnosis, grading, staging and treatment of NEN. These included pathology, radiology, endoscopy and molecular imaging procedures. In an iterative process, a synoptic reporting template for molecular imaging procedures was developed to guide personalised therapies. Following pilot implementation and refinement within the ENETS Center of Excellence network, harmonisation with specialist imaging societies including the Society of Nuclear Medicine, European Association of Nuclear Medicine and the International Cancer Imaging Society will be pursued., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Purpose: Selective internal radiation therapy (SIRT) requires a good liver registration of multi-modality images to obtain precise dose prediction and measurement. This study investigated the feasibility of liver registration of CT and MR images, guided by segmentation of the liver and its landmarks. The influence of the resulting lesion registration on dose estimation was evaluated., Methods: The liver segmentation was done with a convolutional neural network (CNN), and the landmarks were segmented manually. Our image-based registration software and its liver-segmentation-guided extension (CNN-guided) were tuned and evaluated with 49 CT and 26 MR images from 20 SIRT patients. Each liver registration was evaluated by the root mean square distance (RMSD) of mean surface distance between manually delineated liver contours and mass center distance between manually delineated landmarks (lesions, clips, etc.). The root mean square of RMSDs (RRMSD) was used to evaluate all liver registrations. The CNN-guided registration was further extended by incorporating landmark segmentations (CNN&LM-guided) to assess the value of additional landmark guidance. To evaluate the influence of segmentation-guided registration on dose estimation, mean dose and volume percentages receiving at least 70 Gy (V70) estimated on the 99m Tc-labeled macro-aggregated albumin ( 99m Tc-MAA) SPECT were computed, either based on lesions from the reference 99m Tc-MAA CT (reference lesions) or from the registered floating CT or MR images (registered lesions) using the CNN- or CNN&LM-guided algorithms., Results: The RRMSD decreased for the floating CTs and MRs by 1.0 mm (11%) and 3.4 mm (34%) using CNN guidance for the image-based registration and by 2.1 mm (26%) and 1.4 mm (21%) using landmark guidance for the CNN-guided registration. The quartiles for the relative mean dose difference (the V70 difference) between the reference and registered lesions and their correlations [25th, 75th; r] are as follows: [- 5.5% (- 1.3%), 5.6% (3.4%); 0.97 (0.95)] and [- 12.3% (- 2.1%), 14.8% (2.9%); 0.96 (0.97)] for the CNN&LM- and CNN-guided CT to CT registrations, [- 7.7% (- 6.6%), 7.0% (3.1%); 0.97 (0.90)] and [- 15.1% (- 11.3%), 2.4% (2.5%); 0.91 (0.78)] for the CNN&LM- and CNN-guided MR to CT registrations., Conclusion: Guidance by CNN liver segmentations and landmarks markedly improves the performance of the image-based registration. The small mean dose change between the reference and registered lesions demonstrates the feasibility of applying the CNN&LM- or CNN-guided registration to volume-level dose prediction. The CNN&LM- and CNN-guided registrations for CTs can be applied to voxel-level dose prediction according to their small V70 change for most lesions. The CNN-guided MR to CT registration still needs to incorporate landmark guidance for smaller change of voxel-level dose estimation., (© 2022. The Author(s).)

Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose-effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.

Purpose: Performing a systematic review and meta-analysis to assess the evidence of intra-arterial therapies in liver metastatic breast cancer (LMBC) patients., Methods: A systemic literature search was performed in PubMed, EMBASE, SCOPUS for studies regarding intra-arterial therapies in LMBC patients. Full text studies of LMBC patients (n ≥ 10) published between January 2010 and December 2020 were included when at least one outcome among response rate, adverse events or survival was available. Response rates were pooled using generalized linear mixed models. A weighted estimate of the population median overall survival (OS) was obtained under the assumption of exponentially distributed survival times., Results: A total of 26 studies (1266 patients) were included. Eleven articles reported on transarterial radioembolization (TARE), ten on transarterial chemoembolization (TACE) and four on chemo-infusion. One retrospective study compared TARE and TACE. Pooled response rates were 49% for TARE (95%CI 32-67%), 34% for TACE (95%CI 22-50%) and 19% for chemo-infusion (95%CI 14-25%). Pooled median survival was 9.2 months (range 6.1-35.4 months) for TARE, 17.8 months (range 4.6-47.0) for TACE and 7.9 months (range 7.0-14.2) for chemo-infusion. No comparison for OS was possible due to missing survival rates at specific time points (1 and 2 year OS) and the large heterogeneity., Conclusion: Although results have to be interpreted with caution due to the large heterogeneity, the superior response rate of TARE and TACE compared to chemo-infusion suggests first choice of TARE or TACE in chemorefractory LMBC patients. Chemo-infusion could be considered in LMBC patients not suitable for TARE or TACE., Level of Evidence: 3a., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Metastatic tumor deposits in bone marrow elicit differential bone responses that vary with the type of malignancy. This results in either sclerotic, lytic, or mixed bone lesions, which can change in morphology due to treatment effects and/or secondary bone remodeling. Hence, morphological imaging is regarded unsuitable for response assessment of bone metastases and in the current Response Evaluation Criteria In Solid Tumors 1.1 (RECIST1.1) guideline bone metastases are deemed unmeasurable. Nevertheless, the advent of functional and molecular imaging modalities such as whole-body magnetic resonance imaging (WB-MRI) and positron emission tomography (PET) has improved the ability for follow-up of bone metastases, regardless of their morphology. Both these modalities not only have improved sensitivity for visual detection of bone lesions, but also allow for objective measurements of bone lesion characteristics. WB-MRI provides a global assessment of skeletal metastases and for a one-step "all-organ" approach of metastatic disease. Novel MRI techniques include diffusion-weighted imaging (DWI) targeting highly cellular lesions, dynamic contrast-enhanced MRI (DCE-MRI) for quantitative assessment of bone lesion vascularization, and multiparametric MRI (mpMRI) combining anatomical and functional sequences. Recommendations for a homogenization of MRI image acquisitions and generalizable response criteria have been developed. For PET, many metabolic and molecular radiotracers are available, some targeting tumor characteristics not confined to cancer type (e.g. 18 F-FDG) while other targeted radiotracers target specific molecular characteristics, such as prostate specific membrane antigen (PSMA) ligands for prostate cancer. Supporting data on quantitative PET analysis regarding repeatability, reproducibility, and harmonization of PET/CT system performance is available. Bone metastases detected on PET and MRI can be quantitatively assessed using validated methodologies, both on a whole-body and individual lesion basis. Both have the advantage of covering not only bone lesions but visceral and nodal lesions as well. Hybrid imaging, combining PET with MRI, may provide complementary parameters on the morphologic, functional, metabolic and molecular level of bone metastases in one examination. For clinical implementation of measuring bone metastases in response assessment using WB-MRI and PET, current RECIST1.1 guidelines need to be adapted. This review summarizes available data and insights into imaging of bone metastases using MRI and PET., Competing Interests: KH reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, all outside the submitted work. CD reports consultancy for Sirtex, Terumo and PSI CRO, speaker fees from Terumo and Advanced Accelerator Applications and is a member of advisory board for Terumo and Ipsen. EL reports grants from Fondazione AIRC and Italian Ministry of Health, royalties from Springer, lecturer fees from MI&T congressi and ESMIT. LF reports speaker fees from Sanofi, Novartis, Jannssen, and General Electric, congress sponsorship from Guerbet, industrial grant on radiomics from Invectys and Novartis, and co-investigator in grant with Philips, Ariana Pharma, Evolucare. The remaining 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 Oprea-Lager, Cysouw, Boellaard, Deroose, de Geus-Oei, Lopci, Bidaut, Herrmann, Fournier, Bäuerle, deSouza and Lecouvet.)

A 76-y-old man with hypoosmolar hyponatremia of unknown origin was referred to the nuclear medicine department for 18 F-FDG PET/CT to exclude a malignant cause. Increased 18 F-FDG uptake in both adrenal glands was observed and investigated., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Positron emission tomography (PET) imaging of the C-X-C chemokine receptor 4 (CXCR4) with [ 68 Ga]PentixaFor has intrinsic diagnostic value and is used to select patients for personalized CXCR4-targeted radionuclide therapy with its therapeutic radiopharmaceutical companion [ 177 Lu]PentixaTher. However, a CXCR4-targeting radiopharmaceutical labeled with fluorine-18 is still of high value due to its favorable characteristics over gallium-68. Furthermore, clinical results with [ 177 Lu]PentixaTher are promising, but there is still room for improvement regarding pharmacokinetics and dosimetry profile. Therefore, this study aimed to develop innovative CXCR4-targeting radiopharmaceuticals, both for diagnostic and therapeutic purposes, starting from a D-amino acid-based peptide probe (DV1-k-(DV3)) that conserves high CXCR4 binding affinity after radiolabeling. AlF-NOTA-DV1-k-(DV3) showed similar in vitro binding affinity to human CXCR4 (hCXCR4) compared to [ nat Ga]PentixaFor (half-maximal inhibitory concentration (IC 50 ): 5.3 ± 0.9 nM and 8.6 ± 1.1 nM, respectively) and also binds to murine CXCR4 (mCXCR4) (IC 50 : 33.4 ± 13.5 nM) while [ nat Ga]PentixaFor is selective for hCXCR4 (IC 50 > 1000 nM for mCXCR4). Both the diagnostic radiotracers based on the DV1-k-(DV3) vector platform, [ 18 F]AlF-NOTA-DV1-k-(DV3) and [ 68 Ga]Ga-DOTA-DV1-k-(DV3), and their therapeutic companion [ 177 Lu]Lu-DOTA-DV1-k-(DV3) were successfully produced in high yield, demonstrated high in vitro and in vivo stability, and have the same favorable pharmacokinetic profile. Furthermore, in wild-type mice and a hCXCR4-expressing tumor model, [ 18 F]AlF-NOTA-DV1-k-(DV3) shows CXCR4-specific targeting in mCXCR4-expressing organs such as liver (mean standardized uptake value (SUV mean ) 8.2 ± 1.0 at 75 min post-injection (p.i.)), spleen (SUV mean 2.5 ± 1.0 at 75 min p.i.), and bone (SUV mean 0.4 ± 0.1 at 75 min p.i., femur harboring bone marrow) that can be blocked with the CXCR4 antagonist AMD3100. However, in a hCXCR4-expressing tumor model, tumor uptake of [ 18 F]AlF-NOTA-DV1-k-(DV3) was significantly lower (SUV mean 0.6 ± 0.2) compared to [ 68 Ga]PentixaFor (SUV mean 2.9). This might be explained by the high affinity of [ 18 F]AlF-NOTA-DV1-k-(DV3) toward both mCXCR4 and hCXCR4. High mCXCR4 expression in mouse liver results in a large fraction of [ 18 F]AlF-NOTA-DV1-k-(DV3) that is sequestered to the liver, resulting despite its similar in vitro affinity for hCXCR4, in lower tumor accumulation compared to [ 68 Ga]PentixaFor. As CXCR4 is not expressed in healthy human liver, the findings in mice are not predictive for the potential clinical performance of this novel class of CXCR4-targeting radiotracers. In conclusion, the DV1-k-(DV3) scaffold is a promising vector platform for translational CXCR4-directed research.

Abstract: A 56-year-old woman presented with right iliac fossa pain. Abdominal CT showed a mesenteric mass in the right iliac fossa, adjacent to the vena cava inferior and right ureter. Biopsy of the mass revealed a well-differentiated neuroendocrine tumor. 68Ga-DOTATATE PET/CT showed strong somatostatin receptor expression only within in a small, central area of this mesenteric mass, with faint 68Ga-DOTATATE uptake in the majority of this mesenteric mass. Pathology revealed an IgG4-positive storiform fibrosis surrounding a mesenteric adenopathy. 68Ga-DOTATATE PET/CT discriminates between neuroendocrine tumor lymph node metastases and fibrosis, hereby avoiding potential sampling error of tumor biopsies and guiding surgical approach., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Targeted radionuclide therapy (TRNT) is a promising approach for cancer therapy. Terbium has four medically interesting isotopes ( 149 Tb, 152 Tb, 155 Tb and 161 Tb) which span the entire radiopharmaceutical space (TRNT, PET and SPECT imaging). Since the same element is used, accessing the various diagnostic or therapeutic properties without changing radiochemical procedures and pharmacokinetic properties is advantageous. The use of (heat-sensitive) biomolecules as vector molecule with high affinity and selectivity for a certain molecular target is promising. However, mild radiolabeling conditions are required to prevent thermal degradation of the biomolecule. Herein, we report the evaluation of potential bifunctional chelators for Tb-labeling of heat-sensitive biomolecules using human serum albumin (HSA) to assess the in vivo stability of the constructs. p -SCN-Bn-CHX-A"-DTPA, p -SCN-Bn-DOTA, p -NCS-Bz-DOTA-GA and p -SCN-3 p -C-NETA were conjugated to HSA via a lysine coupling method. All HSA-constructs were labeled with [ 161 Tb]TbCl 3 at 40°C with radiochemical yields higher than 98%. The radiolabeled constructs were stable in human serum up to 24 h at 37°C. 161 Tb-HSA-constructs were injected in mice to evaluate their in vivo stability. Increasing bone accumulation as a function of time was observed for [ 161 Tb]TbCl 3 and [ 161 Tb]Tb-DTPA-CHX-A"-Bn-HSA, while negligible bone uptake was observed with the DOTA, DOTA-GA and NETA variants over a 7-day period. The results indicate that the p -SCN-Bn-DOTA, p -NCS-Bz-DOTA-GA and p -SCN-3 p -C-NETA are suitable bifunctional ligands for Tb-based radiopharmaceuticals, allowing for high yield radiolabeling in mild conditions., 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 Cassells, Ahenkorah, Burgoyne, Van de Voorde, Deroose, Cardinaels, Bormans, Ooms and Cleeren.)

Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory., (© 2021. The Author(s).)