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Purpose To assess the impact of an [18F]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology. Methods In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [18F]FDG-PET/CT and were randomised to an [18F]FDG-PET/CT-driven or diagnostic surgery group. In the [18F]FDG-PET/CT-driven group, management was based on the [18F]FDG-PET/CT result: when the index nodule was visually [18F]FDG-positive, diagnostic surgery was advised; when [18F]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hürthle cell and Hürthle cell nodules. Results Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32–53%]) of patients in the [18F]FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68–93%]) in the diagnostic surgery group (p < 0.001). [18F]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28–53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33–63%]) in non-Hürthle cell and 13% (2/15 [95% CI, 2–40%]) in Hürthle cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [18F]FDG-PET/CT were 94.1% (80.3–99.3%), 39.8% (30.0–50.2%), 95.1% (83.5–99.4%), 35.2% (25.4–45.9%), and 31.1% (23.3–39.7%), respectively. Conclusion An [18F]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hürthle cell nodules. Trial registration number This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

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.

Tumor delineation using noninvasive medical imaging modalities is important to determine the target volume in radiation treatment planning and to evaluate treatment response. It is expected that combined use of CT and functional information from 18 F-FDG PET will improve tumor delineation. However, until now, tumor delineation using PET has been based on static images of 18 F-FDG standardized uptake values (SUVs). 18 F-FDG uptake depends not only on tumor physiology but also on blood supply, distribution volume, and competitive uptake processes in other tissues. Moreover, 18 F-FDG uptake in tumor tissue and in surrounding healthy tissue depends on the time after injection. Therefore, it is expected that the glucose metabolic rate (MR glu ) derived from dynamic PET scans gives a better representation of the tumor activity than does SUV. The aim of this study was to determine tumor volumes in MR glu maps and to compare them with the values from SUV maps. Methods: Twenty-nine lesions in 16 dynamic 18 F-FDG PET scans in 13 patients with non-small cell lung carcinoma were analyzed. MR glu values were calculated on a voxel-by-voxel basis using the standard 2-compartment 18 F-FDG model with trapping in the linear approximation (Patlak analysis). The blood input function was obtained by arterial sampling. Tumor volumes were determined in SUV maps of the last time frame and in MR glu maps using 3-dimensional isocontours at 50% of the maximum SUV and the maximum MR glu , respectively. Results: Tumor volumes based on SUV contouring ranged from 1.31 to 52.16 cm 3 , with a median of 8.57 cm 3 . Volumes based on MR glu ranged from 0.95 to 37.29 cm 3 , with a median of 3.14 cm 3 . For all lesions, the MR glu volumes were significantly smaller than the SUV volumes. The percentage differences (defined as 100% · (V MR glu 2 V SUV )/V SUV , where V is volume) ranged from 212.8% to 284.8%, with a median of 232.8%. Conclusion: Tumor volumes from MR glu maps were significantly smaller than SUV-based volumes. These findings can be of importance for PET-based radiotherapy planning and therapy response monitoring.

In this study, we examined the in vivo relationship between functional tumor vasculature, determined by dynamic contrast-enhanced (DCE-) MRI, and tumor metabolism, determined by dynamic 18 F-FDG PET, during cytotoxic treatment of patients with colorectal liver metastases. Methods: Twenty-three patients underwent DCE-MRI (using gadolinium dimeglumine) and dynamic 18 F-FDG PET at baseline and after 3 treatment cycles, unless treatment was terminated because of toxicity. Parameters for vasculature (rate constant between extravascular extracellular space and blood plasma [k ep ] and volume transfer constant [K trans ]), extracellular space (v e ), tumor size (the maximal axial diameter of each included lesion [MAD]), and metabolism (glucose metabolic rates [MR glc ]) were derived, and changes during treatment were correlated. Overall survival (OS) and progression-free survival (PFS) served as outcome measures for the predictive abilities of pretreatment parameters and of treatment-related parameter changes. Results: Pretreatment MR glc and MAD were individually predictive for OS and PFS. During treatment, K trans increased significantly, but this increase could not be confirmed in a lesion-by-lesion analysis. MR glc decreased significantly (P , 0.001). No correlations were found for changes in DCE-MRI parameters and DMR glc . No relationship was found between changes in DCE-MRI parameters and OS or PFS. DMR glc was able to predict OS (P 5 0.008) after correction for confounders. Conclusion: The efficacy of cytotoxic chemotherapy assessed by reduction in tumor metabolism does not depend on pretreatment properties of the tumor vasculature determined by DCE-MRI. Cytotoxic chemotherapy does not alter DCE-MRI-derived properties of tumor vasculature but decreases glucose consumption of tumor cells.

Abstract[ 18 F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a useful imaging tool in the evolving management of patients with colorectal carcinoma. This technique is able to measure and visualize metabolic changes in cancer cells. This feature results in the ability to distinguish viable tumor from scar tissue, in the detection of tumor foci at an earlier stage than possible by conventional anatomic imaging and in the measurement of alterations in tumor metabolism, indicative of tumor response to therapy. Nowadays, FDG-PET plays a pivotal role in staging patients before surgical resection of recurrence and metastases, in the localization of recurrence in patients with an unexplained rise in serum carcinoembryonic antigen and in assessment of residual masses after treatment. In the presurgical evaluation, FDG-PET may be best used in conjunction with anatomic imaging in order to combine the benefits of both anatomical (CT) and functional (PET) information, which leads to significant improvements in preoperative liver staging and preoperative judgment on the feasibility of resection. Integration of FDG-PET into the management algorithm of these categories of patients alters and improves therapeutic management, reduces morbidity due to futile surgery, leads to substantial cost savings and probably also to a better patient outcome. FDG-PET also appears to have great potential in monitoring the success of local ablative therapies soon after intervention and in the prediction and evaluation of response to radiotherapy, systemic therapy, and combinations thereof. This review aims to outline the current and future role of FDG-PET in the field of colorectal cancer.

SARS-CoV-2 may cause acute respiratory disease, but the infection can also initiate neurological symptoms. Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus' capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans Lewy body formation is an indication for the development of Parkinson's disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection.