Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging.

BACKGROUND: Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). AIMS: To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods. METHODS: This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE. RESULTS: Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA1c were also observed with semaglutide. CONCLUSIONS: The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

Hybrid PET/MRI in non-small cell lung cancer (NSCLC) and lung nodules-a literature review.

BACKGROUND: The use of hybrid PET/MRI for clinical staging is growing in several cancer forms and, consequently, PET/MRI has also gained interest in the assessment of non-small cell lung cancer (NSCLC) and lung lesions. However, lung evaluation with PET/MRI is associated with challenges related to technical issues and diagnostic image quality. We, therefore, investigated the published literature on PET/MRI for clinical staging in NSCLC or lung nodule detection specifically addressing diagnostic accuracy and technical issues. METHODS: The data originates from a systematic search performed in PubMed/MEDLINE, Embase, and Cochrane Library on hybrid PET/MRI in patients with cancer for a scoping review published earlier ( https://doi.org/10.1007/s00259-019-04402-8 ). Studies in English and German evaluating the diagnostic performance of hybrid PET/MRI for NSCLC or lung nodule detection in cancer patients were selected. Data reported in peer-reviewed journals without restrictions to year of publication were included. RESULTS: A total of 3138 publications were identified from which 116 published 2012-2018 were included. Of these, nine studies addressed PET/MRI in NSCLC (4) or lung nodule detection (5). Overall, PET/MRI did not provide advantages in preoperative T- and N-staging in NSCLC compared to PET/CT. The data on M-staging were too few for conclusions to be drawn. The lung nodule detection rate of PET/MRI was comparable to that of PET/CT for FDG-avid nodules larger than 10 mm, but the sensitivity of PET/MRI for detection of non-FDG-avid nodules smaller than 5 mm was low. CONCLUSION: PET/MRI did not provide advantages in T- and N-staging of NSCLC compared to PET/CT. PET/MRI had a comparable sensitivity for detection of FDG-avid lung nodules and nodules over 10 mm, but PET/CT yielded a higher detection rate in non FDG-avid lung nodules under 5 mm. With PET/MRI, the overall detection rate for lung nodules in various cancer types remains inferior to that of PET/CT due to the lower diagnostic performance of MRI than CT in the lungs.

Clinical Characteristics of a Non-Alcoholic Fatty Liver Disease Population Across the Fibrosis Spectrum Measured by Magnetic Resonance Elastography: Analysis of Screening Data.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is associated with liver-related complications and metabolic comorbidities. The phenotype is wide, ranging from simple steatosis to non-alcoholic steatohepatitis with advanced fibrosis. In this analysis of a phase 1 trial, clinical characteristics of screened subjects with NAFLD were studied according to the extent of fibrosis assessed using magnetic resonance elastography (MRE). METHODS: One hundred ninety-four subjects with body mass index (BMI) of 25-40 kg/m2 and suspected NAFLD were assessed by MRE and grouped by MRE thresholds as a proxy for fibrosis staging (groups 0-4). Data were summarized by group levels, and correlation analyses between MRE values and clinical parameters (including magnetic resonance imaging-proton density fat fraction) were performed. RESULTS: Most subjects had MRE values in the lower range (groups 0-1; N = 148). Type 2 diabetes (T2D) and BMI > 35 kg/m2 were more frequent in groups with higher than lower MRE values. Subjects in the highest MRE groups also tended to be older and have higher liver enzyme concentrations compared with lower MRE groups. No, or weak, correlations were found between MRE values and clinical parameters (all r values ≤ 0.45). CONCLUSIONS: There was considerable variation and overlap in clinical characteristics across the spectrum of liver stiffness. Although groups with high MRE values generally included more subjects with T2D and obesity, and had higher age and concentrations of liver enzymes, the clinical characteristics did not strongly correlate with MRE scores in this population. TRIAL REGISTRATION: Registered on Clinicaltrials.gov on November 29, 2017 (NCT03357380).

Hybrid PET/MRI in major cancers: a scoping review.

PURPOSE: PET/MRI was introduced for clinical use in 2011 and is now an established modality for the imaging of brain and certain pelvic cancers, whereas clinical use for the imaging of other forms of cancer is not yet widespread. We therefore systematically investigated what has been published on the use of PET/MRI compared to PET/CT in the imaging of cancers outside the brain, focusing on clinical areas of application related to diagnosis, staging and restaging. METHODS: A systematic search of PubMed/MEDLINE, Embase and the Cochrane Library was performed. Studies evaluating the diagnostic performance of simultaneous PET/MRI in cancer patients were chosen. RESULTS: A total of 3,138 publications were identified and 116 published during the period 2012-2018 were included and were grouped according to the major cancer forms: 13 head and neck (HNC), 9 breast (BC), 21 prostate (PC), 14 gynaecological, 13 gastrointestinal (GIC), and 46 various cancers. Data from studies comparing PET/MRI and PET/CT for staging/restaging suggested the superiority of 18F-FDG PET/MRI for the detection of tumour extension and retropharyngeal lymph node metastases in nasopharyngeal cancer, and for the detection of liver metastases and possibly bone marrow metastases in high-risk BC. FDG PET/MRI tended to be inferior for the detection of lung metastases in HNC and BC. 68Ga-PSMA-11 PET/MRI was superior to PET/CT for the detection of local PC recurrence. FDG PET/MRI was superior to FDG PET/CT for the detection of local tumour invasion in cervical cancer and had higher accuracy for the detection of liver metastases in colorectal cancer. CONCLUSION: The scoping review methodology resulted in the identification of a huge number of records, of which less than 5% were suitable for inclusion and only a limited number allowed conclusions on the advantages/disadvantages of PET/MRI compared to PET/CT in the oncological setting. There was evidence to support the use of FDG PET/MRI in staging of nasopharyngeal cancer and high-risk BC. Preliminary data indicate the superiority of PET/MRI for the detection of local recurrence in PC, local tumour invasion in cervical cancer, and liver metastases in colorectal cancer. These conclusions are based on small datasets and need to be further explored.

Prognostic modeling for patients with colorectal liver metastases incorporating FDG PET radiomic features.

OBJECTIVE: We aimed to improve prediction of outcome for patients with colorectal liver metastases, via prognostic models incorporating PET-derived measures, including radiomic features that move beyond conventional standard uptake value (SUV) measures. PATIENTS AND METHODS: A range of parameters including volumetric and heterogeneity measures were derived from FDG PET images of 52 patients with colorectal intrahepatic-only metastases (29 males and 23 females; mean age 62.9 years [SD 9.8; range 32-82]). The patients underwent PET/CT imaging as part of the clinical workup prior to final decision on treatment. Univariate and multivariate models were implemented, which included statistical considerations (to discourage false discovery and overfitting), to predict overall survival (OS), progression-free survival (PFS) and event-free survival (EFS). Kaplan-Meier survival analyses were performed, where the subjects were divided into high-risk and low-risk groups, from which the hazard ratios (HR) were computed via Cox proportional hazards regression. RESULTS: Commonly-invoked SUV metrics performed relatively poorly for different prediction tasks (SUVmax HR = 1.48, 0.83 and 1.16; SUVpeak HR = 2.05, 1.93, and 1.64, for OS, PFS and EFS, respectively). By contrast, the number of liver metastases and metabolic tumor volume (MTV) each performed well (with respective HR values of 2.71, 2.61 and 2.42, and 2.62, 1.96 and 2.29, for OS, PFS and EFS). Total lesion glycolysis (TLG) also resulted in similar performance as MTV. Multivariate prognostic modeling incorporating different features (including those quantifying intra-tumor heterogeneity) resulted in further enhanced prediction. Specifically, HR values of 4.29, 4.02 and 3.20 (p-values = 0.00004, 0.0019 and 0.0002) were obtained for OS, PFS and EFS, respectively. CONCLUSIONS: PET-derived measures beyond commonly invoked SUV parameters hold significant potential towards improved prediction of clinical outcome in patients with liver metastases, especially when utilizing multivariate models.

Time and dose-related changes in lung perfusion after definitive radiotherapy for NSCLC.

BACKGROUND AND PURPOSE: To examine radiation-induced changes in regional lung perfusion per dose level in 58 non-small-cell lung cancer (NSCLC) patients treated with intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: NSCLC patients receiving chemo-radiotherapy (RT) of minimum 60 Gy were included prospectively in the study. Lung perfusion single-photon emission computed tomography (SPECT/CT) was performed before and serially after RT. Changes (relative to baseline, %) in regional lung perfusion were correlated with regional dose. Toxicity outcome was radiation pneumonitis (RP) CTC grades 2-5. RESULTS: Perfusion changes were associated with dose. Dose-dependent reduction in regional perfusion was observed at 3, 6 and 12 months of follow-up. Relative perfusion loss per dose bin was 4% at 1 month, 14% at 3 months, 13% at 6 months and 21% at 12 months after RT. In patients with RP, perfusion reduction was larger in high dose lung regions, compared to those without RP. Low dose regions, on the contrary, revealed perfusion gain in the patients with RP. CONCLUSION: Progressive dose dependent perfusion loss is manifested on SPECT up to 12 months following IMRT. These findings suggest that the dynamic change in perfusion may have prognostic value in predicting radiation pneumonitis in NSCLC patients treated with IMRT.

Single photon emission computed tomography (SPECT) and SPECT/low-dose computerized tomography did not increase sensitivity or specificity compared to planar bone scintigraphy for detection of bone metastases in advanced breast cancer.

PURPOSE: To evaluate and compare the diagnostic performance of whole-body planar bone scintigraphy (WBS), single photon emission computed tomography (SPECT), SPECT/low-dose computerized tomography (SPECT/ldCT) and SPECT/contrast enhanced diagnostic CT (SPECT/cdCT) in the staging of patients with advanced breast cancer. METHODS: Seventy-eight patients with recurrence of biopsy-proven breast cancer and suspicion of disseminated disease were investigated with WBS, SPECT, SPECT/ldCT, SPECT/cdCT and MRI performed on the same day in this prospective study. Images were separately analysed in a blinded fashion by radiologists and nuclear medicine physicians regarding the presence of pathological findings. MRI served as reference standard. RESULTS: According to reference standard, 38 of 73 patients had bone metastases. The sensitivity was 87%, 87%, 79%, and 84% and specificity 63%, 71%, 63% and 83% for WBS, SPECT, SPECT/ldCT and SPECT/cdCT. A significantly increased specificity of SPECT/cdCT compared to WBS and SPECT/ldCT was found, and other parameters did not differ significantly between modalities. Additional two patients had bone metastases solely located outside the MRI scan field and seven patients had soft tissue metastases, but no skeletal changes on MRI. CONCLUSION: WBS, SPECT and SPECT/ldCT were less sensitive than MRI and equally specific for the detection of bone metastases in patients with advanced breast cancer. Based on our findings, we suggest that initial staging include WBS, MRI of the spine and CT for soft tissue evaluation. Further studies may clarify the potential benefits of whole-body MRI and 18F-NaF PET/CT or 18F-FDG PET/CT.

Inclusion of functional information from perfusion SPECT improves predictive value of dose-volume parameters in lung toxicity outcome after radiotherapy for non-small cell lung cancer: A prospective study.

BACKGROUND AND PURPOSE: To compare functional and standard dose-volume parameters as predictors of postradiation pulmonary toxicity in lung cancer patients undergoing curative chemo-radiotherapy (RT) studied prospectively. MATERIAL AND METHODS: A total of 58 patients treated with Intensity Modulated RT (60-66Gy) were analysed. Standard dose-volume parameters were extracted from treatment planning computed tomography (CT) scans. Corresponding functional dose-volume parameters were calculated from perfusion single-photon emission computed tomography (SPECT). Primary end-point was radiation pneumonitis (RP) grade 2-5. RESULTS: Functional mean lung dose (MLD) and lung volumes receiving 5, 10, 20 and 30Gy (V5-V30, respectively) revealed high correlation with corresponding standard parameters (r>0.8). Standard MLD, V20 and V30 were significantly higher in patients with RP (p=0.01). All functional parameters were significantly higher in the RP patients (p<0.03). In multivariate analysis functional parameters produced superior risk estimates, while all standard parameters, except V30, were not related to the risk of RP. Area under the curve (AUC) for functional metrics generally exceeded the AUC for corresponding standard parameters, but they were not significantly different from each other. CONCLUSION: SPECT-based functional parameters were better to predict the risk of RP compared to standard CT-based dose-volume parameters. Functional parameters may be useful to guide radiotherapy planning in order to reduce the risk of radiation-induced toxicity.

Loss of lung function after chemo-radiotherapy for NSCLC measured by perfusion SPECT/CT: Correlation with radiation dose and clinical morbidity.

BACKGROUND: The purpose of the study was to assess dose and time dependence of radiotherapy (RT)-induced changes in regional lung function measured with single photon emission computed tomography (SPECT) of the lung and relate these changes to the symptomatic endpoint of radiation pneumonitis (RP) in patients treated for non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: NSCLC patients scheduled to receive curative RT of minimum 60 Gy were included prospectively in the study. Lung perfusion SPECT/CT was performed before and three months after RT. Reconstructed SPECT/CT data were registered to treatment planning CT. Dose to the lung was segmented into regions corresponding to 0-5, 6-20, 21-40, 41-60 and > 60 Gy. Changes (%) in regional lung perfusion before and after RT were correlated with regional dose and symptomatic RP (CTC grade 2-5) outcome. RESULTS: A total of 58 patients were included, of which 45 had three-month follow-up SPECT/CT scans. Analysis showed a statistically significant dose-dependent reduction in regional perfusion at three-month follow-up. The largest population composite perfusion loss was in 41-60 Gy (42.2%) and > 60 Gy (41.7%) dose bins. Lung regions receiving low dose of 0-5 Gy and 6-20 Gy had corresponding perfusion increase (-7.2% and -6.1%, respectively). Regional perfusion reduction was different in patients with and without RP with the largest difference in 21-40 Gy bin (p = 0.02), while for other bins the difference did not reach statistical significance. The risk of symptomatic RP was higher for the patients with perfusion reduction after RT (p = 0.02), with the relative risk estimate of 3.6 (95% CI 1.1-12). CONCLUSION: Perfusion lung function changes in a dose-dependent manner after RT. The severity of radiation-induced lung symptoms is significantly correlated with SPECT perfusion changes. Perfusion reduction early after RT is associated with a high risk of later development of symptomatic RP.

Role of perfusion SPECT in prediction and measurement of pulmonary complications after radiotherapy for lung cancer.

PURPOSE: The purpose of the study was to evaluate the ability of baseline perfusion defect score (DS) on SPECT to predict the development of severe symptomatic radiation pneumonitis (RP) and to evaluate changes in perfusion on SPECT as a method of lung perfusion function assessment after curative radiotherapy (RT) for non-small-cell lung cancer (NSCLC). METHODS: Patients with NSCLC undergoing curative RT were included prospectively. Perfusion SPECT/CT and global pulmonary function tests (PFT) were performed before RT and four times during follow-up. Functional activity on SPECT was measured using a semiquantitative perfusion DS. Pulmonary morbidity was graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4 for pneumonitis. Patients were divided into two groups according to the severity of RP. RESULTS: A total of 71 consecutive patients were included in the study. Baseline DS was associated with chronic obstructive pulmonary disease. A significant inverse correlation was found between baseline DS and forced expiratory volume in 1 s and diffusing capacity of the lung for carbon monoxide. Patients with severe RP had significantly higher baseline total lung DS (mean 5.43) than those with no or mild symptoms (mean DS 3.96, p < 0.01). PFT results were not different between these two groups. The odds ratio for total lung DS was 7.8 (95% CI 1.9 - 31) demonstrating the ability of this parameter to predict severe RP. Adjustment for other potential confounders known to be associated with increased risk of RP was performed and did not change the odds ratio. The median follow-up time after RT was 8.4 months. The largest DS increase of 13.3% was associated with severe RP at 3 months of follow-up (p < 0.01). The development of severe RP during follow-up was not associated with changes in PFT results. CONCLUSION: Perfusion SPECT is a valuable method for predicting severe RP and for assessing changes in regional functional perfusion after curative RT comparable with global PFT.

Detecting reduced renal function in children: comparison of GFR-models and serum markers.

BACKGROUND: The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR)-models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results. METHODS: Glomerular filtration rate was measured by plasma clearance of (51)Cr-EDTA (13.7-147.4 mL/min/1.73 m(2)) in 119 children (age range 2.3-14.9 years). Reduced renal function was defined as a GFR of <82 mL/min/1.73 m(2). SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone. RESULTS: The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629-637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221-230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50-57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other variables (P < 0.01), with the BCM-model performing the best (P < 0.05). The SCr-based Schwartz formula and SCr-ratio both performed better than SCr and SCysC. CONCLUSIONS: Among the 119 children enrolled in this study and the renal indicators tested, the BCM-model had the best diagnostic performance in terms of screening for normal or reduced renal function, and the SCr-ratio was a superior diagnostic tool to both SCr and SCysC.

[Diagnostics and treatment of differentiated thyroid cancer using nuclear medicine]. / Nuklearmedicinsk billeddiagnostik og behandling ved differentieret thyroideacancer.

Differentiated thyroid cancer (DTC) is a rare cancer with excellent prognosis for most patients. Primary treatment is surgery. Adjuvant radioiodine is used after surgery and in case of residual radioiodine positive disease. Measurements of serum thyroglobulin levels and neck ultrasound (US) are the primary follow-up procedures. For suspected recurrence, US, computed tomography (CT), radioiodine single photon emission computed tomography/CT, and FDG positron emission tomography/CT will be appropriate choices for restaging and further treatment planning. Multidisciplinary collaboration is crucial for optimal management of patients with DTC.

GFR prediction from cystatin C and creatinine in children: effect of including body cell mass.

BACKGROUND: Aiming to develop a more accurate cystatin C-based model for estimation of glomerular filtration rate (GFR) in children, we hypothesized that inclusion of body cell mass (BCM) would increase the accuracy of the GFR estimate in comparison to a well-established GFR reference method. STUDY DESIGN: Diagnostic test accuracy study. SETTINGS & PARTICIPANTS: 119 children (mean age, 8.8; range, 2.3-14.9 years) referred for GFR measurement by chromium 51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) clearance (mean GFR, 98; range, 13.7-147.4 mL/min/1.73 m(2)). INDEX TEST: GFR estimations by the 2 prediction models resulting from theoretical considerations corroborated by forward stepwise variable selection: GFR (mL/min) = 0.542 × (BCM/SCysC)(0.40) × (height × BSA/SCr)(0.65) and GFR (mL/min) = 0.426 × (weight/SCysC)(0.39) × (height × BSA/SCr)(0.64), where SCysC is serum cystatin C level, BSA is body surface area, and SCr is serum creatinine level. The accuracy and precision of these models were compared with 7 previously published prediction models using random subsampling cross-validation. Local constants and coefficients were calculated for all models. Root mean square error, R(2), and percentage of predictions within ±10% and ±30% of the reference GFR were calculated for all models. Based on 1,000 runs of the cross-validation procedure, median values and 2.5th and 97.5th quantiles of the validation parameters were calculated. REFERENCE TEST: GFR measurement by (51)Cr-EDTA clearance. RESULTS: The BCM model predicted 98% within ±30% of reference GFR and 66% within ±10%, which was higher than for any other model. The weight model predicted 97.5% within ±30% of reference GFR and 62% within ±10%. The BCM model had the highest R(2) and the smallest root mean square error. LIMITATIONS: Included only 9 children with GFR <60 mL/min/1.73 m(2). Lack of independent validation cohort. CONCLUSIONS: The novel BCM model predicts GFR with higher accuracy than previously published models. The weight model is almost as accurate as the BCM model and allows for GFR estimation without knowledge of BCM. However, endogenous methods are still not sufficiently accurate to replace exogenous markers when GFR must be determined with high accuracy.