Metabolic profiling of galectin-1 and galectin-3: a cross-sectional, multi-omics, association study.

OBJECTIVES: Experimental studies indicate a role for galectin-1 and galectin-3 in metabolic disease, but clinical evidence from larger populations is limited. METHODS: We measured circulating levels of galectin-1 and galectin-3 in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study, participants (n = 502, all aged 50 years) and characterized the individual association profiles with metabolic markers, including clinical measures, metabolomics, adipose tissue distribution (Imiomics) and proteomics. RESULTS: Galectin-1 and galectin-3 were associated with fatty acids, lipoproteins and triglycerides including lipid measurements in the metabolomics analysis adjusted for body mass index (BMI). Galectin-1 was associated with several measurements of adiposity, insulin secretion and insulin sensitivity, while galectin-3 was associated with triglyceride-glucose index (TyG) and fasting insulin levels. Both galectins were associated with inflammatory pathways and fatty acid binding protein (FABP)4 and -5-regulated triglyceride metabolic pathways. Galectin-1 was also associated with several proteins related to adipose tissue differentiation. CONCLUSIONS: The association profiles for galectin-1 and galectin-3 indicate overlapping metabolic effects in humans, while the distinctly different associations seen with fat mass, fat distribution, and adipose tissue differentiation markers may suggest a functional role of galectin-1 in obesity.

Voxel-wise body composition analysis using image registration of a three-slice CT imaging protocol: methodology and proof-of-concept studies.

BACKGROUND: Computed tomography (CT) is an imaging modality commonly used for studies of internal body structures and very useful for detailed studies of body composition. The aim of this study was to develop and evaluate a fully automatic image registration framework for inter-subject CT slice registration. The aim was also to use the results, in a set of proof-of-concept studies, for voxel-wise statistical body composition analysis (Imiomics) of correlations between imaging and non-imaging data. METHODS: The current study utilized three single-slice CT images of the liver, abdomen, and thigh from two large cohort studies, SCAPIS and IGT. The image registration method developed and evaluated used both CT images together with image-derived tissue and organ segmentation masks. To evaluate the performance of the registration method, a set of baseline 3-single-slice CT images (from 2780 subjects including 8285 slices) from the SCAPIS and IGT cohorts were registered. Vector magnitude and intensity magnitude error indicating inverse consistency were used for evaluation. Image registration results were further used for voxel-wise analysis of associations between the CT images (as represented by tissue volume from Hounsfield unit and Jacobian determinant) and various explicit measurements of various tissues, fat depots, and organs collected in both cohort studies. RESULTS: Our findings demonstrated that the key organs and anatomical structures were registered appropriately. The evaluation parameters of inverse consistency, such as vector magnitude and intensity magnitude error, were on average less than 3 mm and 50 Hounsfield units. The registration followed by Imiomics analysis enabled the examination of associations between various explicit measurements (liver, spleen, abdominal muscle, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), thigh SAT, intermuscular adipose tissue (IMAT), and thigh muscle) and the voxel-wise image information. CONCLUSION: The developed and evaluated framework allows accurate image registrations of the collected three single-slice CT images and enables detailed voxel-wise studies of associations between body composition and associated diseases and risk factors.

Spleen volume is independently associated with non-alcoholic fatty liver disease, liver volume and liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) can lead to irreversible liver damage manifesting in systemic effects (e.g., elevated portal vein pressure and splenomegaly) with increased risk of deadly outcomes. However, the association of spleen volume with NAFLD and related type 2-diabetes (T2D) is not fully understood. The UK Biobank contains comprehensive health-data of 500,000 participants, including clinical data and MR images of >40,000 individuals. The present study estimated the spleen volume of 37,066 participants through automated deep learning-based image segmentation of neck-to-knee MR images. The aim was to investigate the associations of spleen volume with NAFLD, T2D and liver fibrosis, while adjusting for natural confounders. The recent redefinition and new designation of NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD), promoted by major organisations of studies on liver disease, was not employed as introduced after the conduct of this study. The results showed that spleen volume decreased with age, correlated positively with body size and was smaller in females compared to males. Larger spleens were observed in subjects with NAFLD and T2D compared to controls. Spleen volume was also positively and independently associated with liver fat fraction, liver volume and the fibrosis-4 score, with notable volumetric increases already at low liver fat fractions and volumes, but not independently associated with T2D. These results suggest a link between spleen volume and NAFLD already at an early stage of the disease, potentially due to initial rise in portal vein pressure.

Overfeeding polyunsaturated fat compared with saturated fat does not differentially influence lean tissue accumulation in individuals with overweight: a randomized controlled trial.

BACKGROUND: Fatty acids may influence lean tissue volume and skeletal muscle function. We previously reported in young lean participants that overfeeding PUFA compared with SFA induced greater lean tissue accumulation despite similar weight gain. OBJECTIVES: In a double-blind randomized controlled trial, we aimed to investigate if the differential effects of overfeeding SFA and PUFA on lean tissue accumulation could be replicated in individuals with overweight and identify potential determinants. Further, using substitution models, we investigated associations between SFA and PUFA concentrations with lean tissue volume in a large population-based sample (UK Biobank). METHODS: Sixty-one males and females with overweight [BMI (kg/m2): 27.3 (interquartile range (IQR), 25.4-29.3); age: 43 (IQR, 36-48)] were overfed SFA (palm oil) or n-6 (ω-6) PUFA (sunflower oil) for 8 wk. Lean tissue was assessed by MRI. We had access to n = 13,849 participants with data on diet, covariates, and MRI measurements of lean tissue, as well as 9119 participants with data on circulating fatty acids in the UK Biobank. RESULTS: Body weight gain mean (SD) was similar in PUFA (2.01 ± 1.90 kg) and SFA (2.31 ± 1.38 kg) groups. Lean tissue increased to a similar extent [0.54 ± 0.93 L and 0.67 ± 1.21 L for PUFA and SFA groups, respectively, with a difference between groups of 0.07 (-0.21, 0.35)]. We observed no differential effects on circulating amino acids, myostatin, or IL-15 and no clear determinants of lean tissue accumulation. Similar nonsignificant results for SFA and PUFA were observed in UK Biobank, but circulating fatty acids demonstrated ambiguous and sex-dependent associations. CONCLUSIONS: Overfeeding SFA or PUFA does not differentially affect lean tissue accumulation during 8 wk in individuals with overweight. A lack of dietary fat type-specific effects on lean tissue is supported by specified substitution models in a large population-based cohort consuming their habitual diet. This trial was registered at clinicaltrials.gov identifier as NCT02211612.

Short-term effects of obesity surgery versus low-energy diet on body composition and tissue-specific glucose uptake: a randomised clinical study using whole-body integrated 18F-FDG-PET/MRI.

AIMS/HYPOTHESIS: Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investigate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet low in energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the global and tissue-specific level in individuals with obesity but not diabetes. METHODS: In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding, sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery (n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTT and hyperinsulinaemic-euglycaemic clamps during which concomitant simultaneous whole-body [18F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change. RESULTS: One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight (mean ± SD: -7.7±1.4 kg and -7.4±2.2 kg, respectively), adipose tissue volume (7%) and liver fat content (2% units). HOMA-IR, a main endpoint, was significantly reduced following OS (-26.3% [95% CI -49.5, -3.0], p=0.009) and non-significantly following LCD (-20.9% [95% CI -58.2, 16.5). For both groups, there were similar reductions in triglycerides and LDL-cholesterol. Fasting plasma glucose and insulin were also significantly reduced only following OS. There was an increase in glucose AUC in response to an OGTT in the OS group (by 20%) but not in the LCD group. During hyperinsulinaemia, only the OS group showed a significantly increased PET-derived glucose uptake rate in skeletal muscle but a reduced uptake in the heart and abdominal adipose tissue. Both liver and brain glucose uptake rates were unchanged after surgery or LCD. Whole-body glucose disposal and endogenous glucose production were not significantly affected. CONCLUSIONS/INTERPRETATION: The short-term metabolic effects seen 4 weeks after OS are not explained by loss of body fat alone. Thus OS, but not LCD, led to reductions in fasting plasma glucose and insulin resistance as well as to distinct changes in insulin-stimulated glucose fluxes to different tissues. Such effects may contribute to the prevention or reversal of type 2 diabetes following OS. Moreover, the full effects on whole-body insulin resistance and plasma glucose require a longer time than 4 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT02988011 FUNDING: This work was supported by AstraZeneca R&D, the Swedish Diabetes Foundation, the European Union's Horizon Europe Research project PAS GRAS, the European Commission via the Marie Sklodowska Curie Innovative Training Network TREATMENT, EXODIAB, the Family Ernfors Foundation, the P.O. Zetterling Foundation, Novo Nordisk Foundation, the Agnes and Mac Rudberg Foundation and the Uppsala University Hospital ALF grants.

Improved automated tumor segmentation in whole-body 3D scans using multi-directional 2D projection-based priors.

Early cancer detection, guided by whole-body imaging, is important for the overall survival and well-being of the patients. While various computer-assisted systems have been developed to expedite and enhance cancer diagnostics and longitudinal monitoring, the detection and segmentation of tumors, especially from whole-body scans, remain challenging. To address this, we propose a novel end-to-end automated framework that first generates a tumor probability distribution map (TPDM), incorporating prior information about the tumor characteristics (e.g. size, shape, location). Subsequently, the TPDM is integrated with a state-of-the-art 3D segmentation network along with the original PET/CT or PET/MR images. This aims to produce more meaningful tumor segmentation masks compared to using the baseline 3D segmentation network alone. The proposed method was evaluated on three independent cohorts (autoPET, CAR-T, cHL) of images containing different cancer forms, obtained with different imaging modalities, and acquisition parameters and lesions annotated by different experts. The evaluation demonstrated the superiority of our proposed method over the baseline model by significant margins in terms of Dice coefficient, and lesion-wise sensitivity and precision. Many of the extremely small tumor lesions (i.e. the most difficult to segment) were missed by the baseline model but detected by the proposed model without additional false positives, resulting in clinically more relevant assessments. On average, an improvement of 0.0251 (autoPET), 0.144 (CAR-T), and 0.0528 (cHL) in overall Dice was observed. In conclusion, the proposed TPDM-based approach can be integrated with any state-of-the-art 3D UNET with potentially more accurate and robust segmentation results.

Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Comparison of quantitative [11C]PE2I brain PET studies between an integrated PET/MR and a stand-alone PET system.

PET/MR systems demanded great efforts for accurate attenuation correction (AC) but differences in technology, geometry and hardware attenuation may also affect quantitative results. Dedicated PET systems using transmission-based AC are regarded as the gold standard for quantitative brain PET. The study aim was to investigate the agreement between quantitative PET outcomes from a PET/MR scanner against a stand-alone PET system. Nine patients with Parkinsonism underwent two 80-min dynamic PET scans with the dopamine transporter ligand [11C]PE2I. Images were reconstructed with resolution-matched settings using 68Ge-transmission (stand-alone PET), and zero-echo-time MR (PET/MR) scans for AC. Non-displaceable binding potential (BPND) and relative delivery (R1) were evaluated using volumes of interest and voxel-wise analysis. Correlations between systems were high (r ≥ 0.85) for both quantitative outcome parameters in all brain regions. Striatal BPND was significantly lower on PET/MR than on stand-alone PET (-7%). R1 was significantly overestimated in posterior cortical regions (9%) and underestimated in striatal (-9%) and limbic areas (-6%). The voxel-wise evaluation revealed that the MR-safe headphones caused a negative bias in both parametric BPND and R1 images. Additionally, a significant positive bias of R1 was found in the auditory cortex, most likely due to the acoustic background noise during MR imaging. The relative bias of the quantitative [11C]PE2I PET data acquired from a SIGNA PET/MR system was in the same order as the expected test-retest reproducibility of [11C]PE2I BPND and R1, compared to a stand-alone ECAT PET scanner. MR headphones and background noise are potential sources of error in functional PET/MR studies.

Spatial mapping of tumor heterogeneity in whole-body PET-CT: a feasibility study.

BACKGROUND: Tumor heterogeneity is recognized as a predictor of treatment response and patient outcome. Quantification of tumor heterogeneity across all scales may therefore provide critical insight that ultimately improves cancer management. METHODS: An image registration-based framework for the study of tumor heterogeneity in whole-body images was evaluated on a dataset of 490 FDG-PET-CT images of lung cancer, lymphoma, and melanoma patients. Voxel-, lesion- and subject-level features were extracted from the subjects' segmented lesion masks and mapped to female and male template spaces for voxel-wise analysis. Resulting lesion feature maps of the three subsets of cancer patients were studied visually and quantitatively. Lesion volumes and lesion distances in subject spaces were compared with resulting properties in template space. The strength of the association between subject and template space for these properties was evaluated with Pearson's correlation coefficient. RESULTS: Spatial heterogeneity in terms of lesion frequency distribution in the body, metabolic activity, and lesion volume was seen between the three subsets of cancer patients. Lesion feature maps showed anatomical locations with low versus high mean feature value among lesions sampled in space and also highlighted sites with high variation between lesions in each cancer subset. Spatial properties of the lesion masks in subject space correlated strongly with the same properties measured in template space (lesion volume, R = 0.986, p < 0.001; total metabolic volume, R = 0.988, p < 0.001; maximum within-patient lesion distance, R = 0.997, p < 0.001). Lesion volume and total metabolic volume increased on average from subject to template space (lesion volume, 3.1 ± 52 ml; total metabolic volume, 53.9 ± 229 ml). Pair-wise lesion distance decreased on average by 0.1 ± 1.6 cm and maximum within-patient lesion distance increased on average by 0.5 ± 2.1 cm from subject to template space. CONCLUSIONS: Spatial tumor heterogeneity between subsets of interest in cancer cohorts can successfully be explored in whole-body PET-CT images within the proposed framework. Whole-body studies are, however, especially prone to suffer from regional variation in lesion frequency, and thus statistical power, due to the non-uniform distribution of lesions across a large field of view.

A whole-body diffusion MRI normal atlas: development, evaluation and initial use.

BACKGROUND: Statistical atlases can provide population-based descriptions of healthy volunteers and/or patients and can be used for region- and voxel-based analysis. This work aims to develop whole-body diffusion atlases of healthy volunteers scanned at 1.5T and 3T. Further aims include evaluating the atlases by establishing whole-body Apparent Diffusion Coefficient (ADC) values of healthy tissues and including healthy tissue deviations in an automated tumour segmentation task. METHODS: Multi-station whole-body Diffusion Weighted Imaging (DWI) and water-fat Magnetic Resonance Imaging (MRI) of healthy volunteers (n = 45) were acquired at 1.5T (n = 38) and/or 3T (n = 29), with test-retest imaging for five subjects per scanner. Using deformable image registration, whole-body MRI data was registered and composed into normal atlases. Healthy tissue ADCmean was manually measured for ten tissues, with test-retest percentage Repeatability Coefficient (%RC), and effect of age, sex and scanner assessed. Voxel-wise whole-body analyses using the normal atlases were studied with ADC correlation analyses and an automated tumour segmentation task. For the latter, lymphoma patient MRI scans (n = 40) with and without information about healthy tissue deviations were entered into a 3D U-Net architecture. RESULTS: Sex- and Body Mass Index (BMI)-stratified whole-body high b-value DWI and ADC normal atlases were created at 1.5T and 3T. %RC of healthy tissue ADCmean varied depending on tissue assessed (4-48% at 1.5T, 6-70% at 3T). Scanner differences in ADCmean were visualised in Bland-Altman analyses of dually scanned subjects. Sex differences were measurable for liver, muscle and bone at 1.5T, and muscle at 3T. Volume of Interest (VOI)-based multiple linear regression, and voxel-based correlations in normal atlas space, showed that age and ADC were negatively associated for liver and bone at 1.5T, and positively associated with brain tissue at 1.5T and 3T. Adding voxel-wise information about healthy tissue deviations in an automated tumour segmentation task gave numerical improvements in the segmentation metrics Dice score, sensitivity and precision. CONCLUSIONS: Whole-body DWI and ADC normal atlases were created at 1.5T and 3T, and applied in whole-body voxel-wise analyses.

Automatic segmentation of large-scale CT image datasets for detailed body composition analysis.

BACKGROUND: Body composition (BC) is an important factor in determining the risk of type 2-diabetes and cardiovascular disease. Computed tomography (CT) is a useful imaging technique for studying BC, however manual segmentation of CT images is time-consuming and subjective. The purpose of this study is to develop and evaluate fully automated segmentation techniques applicable to a 3-slice CT imaging protocol, consisting of single slices at the level of the liver, abdomen, and thigh, allowing detailed analysis of numerous tissues and organs. METHODS: The study used more than 4000 CT subjects acquired from the large-scale SCAPIS and IGT cohort to train and evaluate four convolutional neural network based architectures: ResUNET, UNET++, Ghost-UNET, and the proposed Ghost-UNET++. The segmentation techniques were developed and evaluated for automated segmentation of the liver, spleen, skeletal muscle, bone marrow, cortical bone, and various adipose tissue depots, including visceral (VAT), intraperitoneal (IPAT), retroperitoneal (RPAT), subcutaneous (SAT), deep (DSAT), and superficial SAT (SSAT), as well as intermuscular adipose tissue (IMAT). The models were trained and validated for each target using tenfold cross-validation and test sets. RESULTS: The Dice scores on cross validation in SCAPIS were: ResUNET 0.964 (0.909-0.996), UNET++ 0.981 (0.927-0.996), Ghost-UNET 0.961 (0.904-0.991), and Ghost-UNET++ 0.968 (0.910-0.994). All four models showed relatively strong results, however UNET++ had the best performance overall. Ghost-UNET++ performed competitively compared to UNET++ and showed a more computationally efficient approach. CONCLUSION: Fully automated segmentation techniques can be successfully applied to a 3-slice CT imaging protocol to analyze multiple tissues and organs related to BC. The overall best performance was achieved by UNET++, against which Ghost-UNET++ showed competitive results based on a more computationally efficient approach. The use of fully automated segmentation methods can reduce analysis time and provide objective results in large-scale studies of BC.

Single-Cell RNA Analysis Reveals Cell-Intrinsic Functions of CAR T Cells Correlating with Response in a Phase II Study of Lymphoma Patients.

PURPOSE: Although CD19 chimeric antigen receptor T cells (CAR-T) therapy has shown remarkable success in B-cell malignancies, a substantial fraction of patients do not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T infusion products. PATIENTS AND METHODS: In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry. RESULTS: Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product. CONCLUSIONS: We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.

International EANM-SNMMI-ISMRM consensus recommendation for PET/MRI in oncology.

PREAMBLE: The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. The merged International Society for Magnetic Resonance in Medicine (ISMRM) is an international, nonprofit, scientific association whose purpose is to promote communication, research, development, and applications in the field of magnetic resonance in medicine and biology and other related topics and to develop and provide channels and facilities for continuing education in the field.The ISMRM was founded in 1994 through the merger of the Society of Magnetic Resonance in Medicine and the Society of Magnetic Resonance Imaging. SNMMI, ISMRM, and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine and/or magnetic resonance imaging. The SNMMI, ISMRM, and EANM will periodically define new guidelines for nuclear medicine practice to help advance the science of nuclear medicine and/or magnetic resonance imaging and to improve the quality of service to patients throughout the world. Existing practice guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each practice guideline, representing a policy statement by the SNMMI/EANM/ISMRM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI, ISMRM, and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging and magnetic resonance imaging requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guideline by those entities not providing these services is not authorized. These guidelines are an educational tool designed to assist practitioners in providing appropriate care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI, the ISMRM, and the EANM caution against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician or medical physicist in light of all the circumstances presented. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the guidelines. The practice of medicine includes both the art and the science of the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognized that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

Ultrasound Contrast Agent Priming of Biopsy and Introducer Needles by Using a Small Syringe to Improve Needle Visibility in a Phantom Model.

PURPOSE: Biopsy under the guidance of contrast-enhanced ultrasound is sometimes useful. Needle visualization in contrast-specific imaging-mode is often poor; however, it may be improved by priming the needles with an ultrasound contrast agent. This study aimed to evaluate needle priming methods using the ultrasound contrast agent sulfur hexafluoride and a 1 mL syringe. MATERIAL AND METHODS: Two kinds of biopsy needles, side-notch and full core, and one kind of introducer needle were primed using non-primed needles as controls (n = 180). Recordings of punctures were performed in a water bath phantom to which the ultrasound contrast agent had also been added. Contrast-specific imaging-mode needle visibility was evaluated for the entire needles and the needle tips, respectively, quantitatively by calculating the contrast-to-noise ratio and qualitatively via grading by three radiologists. RESULTS: The contrast-to-noise ratio following the ultrasound contrast agent priming was superior compared to the controls for the entire needles of all three types (p < 0.001) and for the needle tips of the core biopsy needles and introducer needles (p < 0.001). However, the ratio was equal to the controls for the needle tips of the side-notch biopsy needles (p = 0.19). Needle visibility following the ultrasound contrast agent priming was qualitatively superior compared to the controls for both the entire needles and the needle tips, and the difference was considered clinically relevant by the assessors (p < 0.001). CONCLUSION: The ultrasound contrast agent needle priming methods described increased the contrast-specific imaging-mode needle visibility in a phantom model. Nonetheless, the results also need to be confirmed in vivo.

Whole body FDG PET/MR for progression free and overall survival prediction in patients with relapsed/refractory large B-cell lymphomas undergoing CAR T-cell therapy.

BACKGROUND: To find semi-quantitative and quantitative Positron Emission Tomography/Magnetic Resonance (PET/MR) imaging metrics of both tumor and non-malignant lymphoid tissue (bone marrow and spleen) for Progression Free Survival (PFS) and Overall Survival (OS) prediction in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) undergoing Chimeric Antigen Receptor (CAR) T-cell therapy. METHODS: A single-center prospective study of 16 r/r LBCL patients undergoing CD19-targeted CAR T-cell therapy. Whole body 18F-fluorodeoxyglucose (FDG) PET/MR imaging pre-therapy and 3 weeks post-therapy were followed by manual segmentation of tumors and lymphoid tissues. Semi-quantitative and quantitative metrics were extracted, and the metric-wise rate of change (Δ) between post-therapy and pre-therapy calculated. Tumor metrics included maximum Standardized Uptake Value (SUVmax), mean SUV (SUVmean), Metabolic Tumor Volume (MTV), Tumor Lesion Glycolysis (TLG), structural volume (V), total structural tumor burden (Vtotal) and mean Apparent Diffusion Coefficient (ADCmean). For lymphoid tissues, metrics extracted were SUVmean, mean Fat Fraction (FFmean) and ADCmean for bone marrow, and SUVmean, V and ADCmean for spleen. Univariate Cox regression analysis tested the relationship between extracted metrics and PFS and OS. Survival curves were produced using Kaplan-Meier analysis and compared using the log-rank test, with the median used for dichotomization. Uncorrected p-values < 0.05 were considered statistically significant. Correction for multiple comparisons was performed, with a False Discovery Rate (FDR) < 0.05 considered statistically significant. RESULTS: Pre-therapy (p < 0.05, FDR < 0.05) and Δ (p < 0.05, FDR > 0.05) total tumor burden structural and metabolic metrics were associated with PFS and/or OS. According to Kaplan-Meier analysis, a longer PFS was reached for patients with pre-therapy MTV ≤ 39.5 ml, ΔMTV≤1.35 and ΔTLG≤1.35. ΔSUVmax was associated with PFS (p < 0.05, FDR > 0.05), while ΔADCmean was associated with both PFS and OS (p < 0.05, FDR > 0.05). ΔADCmean > 0.92 gave longer PFS and OS in the Kaplan-Meier analysis. Pre-therapy bone marrow SUVmean was associated with PFS (p < 0.05, FDR < 0.05) and OS (p < 0.05, FDR > 0.05). For bone marrow FDG uptake, patient stratification was possible pre-therapy (SUVmean ≤ 1.8). CONCLUSIONS: MTV, tumor ADCmean and FDG uptake in bone marrow unaffected by tumor infiltration are possible PET/MR parameters for prediction of PFS and OS in r/r LBCL treated with CAR T-cells. TRIAL REGISTRATION: EudraCT 2016-004043-36.

Obesity is associated with coronary artery stenosis independently of metabolic risk factors: The population-based SCAPIS study.

BACKGROUND AND AIMS: Previous studies reported divergent results on whether metabolically healthy obesity is associated with increased coronary artery calcium and carotid plaques. We investigated this in a cross-sectional fashion in a large, well-defined, middle-aged population using coronary CT angiography (CCTA) and carotid ultrasound. METHODS: In the SCAPIS study (50-65 years, 51% female), CCTA and carotid artery ultrasound were performed in 23,674 individuals without clinical atherosclerotic disease. These subjects were divided into six groups according to BMI (normal weight, overweight, obese) and the presence of metabolic syndrome (MetS) according to the NCEP consensus criteria. RESULTS: The severity of coronary artery stenosis was increased in individuals with obesity without MetS compared to normal-weight individuals without MetS (OR 1.47, 95%CI 1.34-1.62; p < 0.0001), even after adjusting for non-HDL-cholesterol and several lifestyle factors. Such difference was not observed for the presence of carotid artery plaques (OR 0.94, 95%CI 0.87-1.02; p = 0.11). Obese or overweight individuals without any MetS criteria (except the waist criterion) showed significantly more pronounced stenosis in the coronary arteries as compared to the normal-weight individuals, while one criterion was needed to show increased plaque prevalence in the carotid arteries. High blood pressure was the most important single criterion for increased atherosclerosis in this respect. CONCLUSIONS: Individuals with obesity without MetS showed increased severity of coronary artery stenosis, but no increased occurrence of carotid artery plaques compared to normal-weight individuals without MetS, further emphasizing that obesity is not a benign condition even in the absence of MetS.

An image registration method for voxel-wise analysis of whole-body oncological PET-CT.

Whole-body positron emission tomography-computed tomography (PET-CT) imaging in oncology provides comprehensive information of each patient's disease status. However, image interpretation of volumetric data is a complex and time-consuming task. In this work, an image registration method targeted towards computer-aided voxel-wise analysis of whole-body PET-CT data was developed. The method used both CT images and tissue segmentation masks in parallel to spatially align images step-by-step. To evaluate its performance, a set of baseline PET-CT images of 131 classical Hodgkin lymphoma (cHL) patients and longitudinal image series of 135 head and neck cancer (HNC) patients were registered between and within subjects according to the proposed method. Results showed that major organs and anatomical structures generally were registered correctly. Whole-body inverse consistency vector and intensity magnitude errors were on average less than 5 mm and 45 Hounsfield units respectively in both registration tasks. Image registration was feasible in time and the nearly automatic pipeline enabled efficient image processing. Metabolic tumor volumes of the cHL patients and registration-derived therapy-related tissue volume change of the HNC patients mapped to template spaces confirmed proof-of-concept. In conclusion, the method established a robust point-correspondence and enabled quantitative visualization of group-wise image features on voxel level.

Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study: idarubicin dose selection, tissue response and survival.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31.

Determinants of hyperglucagonemia in pediatric non-alcoholic fatty liver disease.

Objective: Over the years, non-alcoholic fatty liver (NAFLD) disease has progressed to become the most frequent chronic liver disease in children and adolescents. The full pathology is not yet known, but disease progression leads to cirrhosis and hepatocellular carcinoma. Risk factors included hypercaloric diet, obesity, insulin resistance and genetics. Hyperglucagonemia appears to be a pathophysiological consequence of hepatic steatosis, thus, the hypothesis of the study is that hepatic fat accumulation leads to increased insulin resistance and impaired glucagon metabolism leading to hyperglucagonemia in pediatric NAFLD. Methods: 132 children and adolescents between 10 and 18 years, with varying degrees of obesity, were included in the study. Using Magnetic Resonance Imaging (MRI) average liver fat was determined, and patients were stratified as NAFLD (>5% liver fat content) and non-NAFLD (<5%). All patients underwent a standardized oral glucose tolerance test (OGTT). Additionally, anthropometric parameters (height, weight, BMI, waist circumference, hip circumference) such as lab data including lipid profile (triglycerides, HDL, LDL), liver function parameters (ALT, AST), uric acid, glucose metabolism (fasting insulin and glucagon, HbA1c, glucose 120 min) and indices evaluating insulin resistance (HIRI, SPISE, HOMA-IR, WBISI) were measured. Results: Children and adolescents with NAFLD had significantly higher fasting glucagon values compared to the non-NAFLD cohort (p=0.0079). In the NAFLD cohort univariate analysis of fasting glucagon was associated with BMI-SDS (p<0.01), visceral adipose tissue volume (VAT) (p<0.001), average liver fat content (p<0.001), fasting insulin concentration (p<0.001), triglycerides (p<0.001) and HDL (p=0.034). This correlation equally applied to all insulin indices HOMA-IR, WBISI, HIRI (all p<0.001) and SPISE (p<0.002). Multivariate analysis (R² adjusted 0.509) for the same subgroup identified HIRI (p=0.003) and VAT volume (p=0.017) as the best predictors for hyperglucagonemia. Average liver fat content is predictive in pediatric overweight and obesity but not NAFLD. Conclusions: Children and adolescents with NAFLD have significantly higher fasting plasma glucagon values, which were best predicted by hepatic insulin resistance and visceral adipose tissue, but not average liver fat content.