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Prognostic value of baseline imaging and clinical features in patients with advanced hepatocellular carcinoma.
Öcal, O, Ingrisch, M, Ümütlü, MR, Peynircioglu, B, Loewe, C, van Delden, O, Vandecaveye, V, Gebauer, B, Zech, CJ, Sengel, C, et al
British journal of cancer. 2022;(2):211-218
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AIMS: To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). DESIGN Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin-bilirubin (ALBI) score, liver-spleen ratio <1.5, ascites, pleural effusion and higher bilirubin values were predictors of worse OS, and higher relative liver enhancement, smooth margin and capsule were associated with better OS. LASSO analysis for LD showed satellite lesions, peritumoral hypointensity in hepatobiliary phase, high ALBI score, higher bilirubin values and ascites were predictors of LD, while randomisation to sorafenib arm was associated with lower LD. CONCLUSIONS Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.
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Deep-learning-based synthesis of post-contrast T1-weighted MRI for tumour response assessment in neuro-oncology: a multicentre, retrospective cohort study.
Jayachandran Preetha, C, Meredig, H, Brugnara, G, Mahmutoglu, MA, Foltyn, M, Isensee, F, Kessler, T, Pflüger, I, Schell, M, Neuberger, U, et al
The Lancet. Digital health. 2021;(12):e784-e794
Abstract
BACKGROUND Gadolinium-based contrast agents (GBCAs) are widely used to enhance tissue contrast during MRI scans and play a crucial role in the management of patients with cancer. However, studies have shown gadolinium deposition in the brain after repeated GBCA administration with yet unknown clinical significance. We aimed to assess the feasibility and diagnostic value of synthetic post-contrast T1-weighted MRI generated from pre-contrast MRI sequences through deep convolutional neural networks (dCNN) for tumour response assessment in neuro-oncology. METHODS In this multicentre, retrospective cohort study, we used MRI examinations to train and validate a dCNN for synthesising post-contrast T1-weighted sequences from pre-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. We used MRI scans with availability of these sequences from 775 patients with glioblastoma treated at Heidelberg University Hospital, Heidelberg, Germany (775 MRI examinations); 260 patients who participated in the phase 2 CORE trial (1083 MRI examinations, 59 institutions); and 505 patients who participated in the phase 3 CENTRIC trial (3147 MRI examinations, 149 institutions). Separate training runs to rank the importance of individual sequences and (for a subset) diffusion-weighted imaging were conducted. Independent testing was performed on MRI data from the phase 2 and phase 3 EORTC-26101 trial (521 patients, 1924 MRI examinations, 32 institutions). The similarity between synthetic and true contrast enhancement on post-contrast T1-weighted MRI was quantified using the structural similarity index measure (SSIM). Automated tumour segmentation and volumetric tumour response assessment based on synthetic versus true post-contrast T1-weighted sequences was performed in the EORTC-26101 trial and agreement was assessed with Kaplan-Meier plots. FINDINGS The median SSIM score for predicting contrast enhancement on synthetic post-contrast T1-weighted sequences in the EORTC-26101 test set was 0·818 (95% CI 0·817-0·820). Segmentation of the contrast-enhancing tumour from synthetic post-contrast T1-weighted sequences yielded a median tumour volume of 6·31 cm3 (5·60 to 7·14), thereby underestimating the true tumour volume by a median of -0·48 cm3 (-0·37 to -0·76) with the concordance correlation coefficient suggesting a strong linear association between tumour volumes derived from synthetic versus true post-contrast T1-weighted sequences (0·782, 0·751-0·807, p<0·0001). Volumetric tumour response assessment in the EORTC-26101 trial showed a median time to progression of 4·2 months (95% CI 4·1-5·2) with synthetic post-contrast T1-weighted and 4·3 months (4·1-5·5) with true post-contrast T1-weighted sequences (p=0·33). The strength of the association between the time to progression as a surrogate endpoint for predicting the patients' overall survival in the EORTC-26101 cohort was similar when derived from synthetic post-contrast T1-weighted sequences (hazard ratio of 1·749, 95% CI 1·282-2·387, p=0·0004) and model C-index (0·667, 0·622-0·708) versus true post-contrast T1-weighted MRI (1·799, 95% CI 1·314-2·464, p=0·0003) and model C-index (0·673, 95% CI 0·626-0·711). INTERPRETATION Generating synthetic post-contrast T1-weighted MRI from pre-contrast MRI using dCNN is feasible and quantification of the contrast-enhancing tumour burden from synthetic post-contrast T1-weighted MRI allows assessment of the patient's response to treatment with no significant difference by comparison with true post-contrast T1-weighted sequences with administration of GBCAs. This finding could guide the application of dCNN in radiology to potentially reduce the necessity of GBCA administration. FUNDING Deutsche Forschungsgemeinschaft.
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Evaluation of human cartilage endplate composition using MRI: Spatial variation, association with adjacent disc degeneration, and in vivo repeatability.
Wang, L, Han, M, Wong, J, Zheng, P, Lazar, AA, Krug, R, Fields, AJ
Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2021;(7):1470-1478
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Abstract
Cartilage endplate (CEP) biochemical composition may influence disc degeneration and regeneration. However, evaluating CEP composition in patients remains a challenge. We used T2* mapping from ultrashort echo-time (UTE) magnetic resonance imaging (MRI), which is sensitive to CEP hydration, to investigate spatial variations in CEP T2* values and to determine how CEP T2* values correlate with adjacent disc degeneration. Thirteen human cadavers (56.4 ± 12.7 years) and seven volunteers (36.9 ± 10.9 years) underwent 3T MRI, including UTE and T1ρ mapping sequences. Spatial mappings of T2* values in L4-S1 CEPs were generated from UTE images and compared between subregions. In the abutting discs, mean T1ρ values in the nucleus pulposus were compared between CEPs with high vs low T2* values. To assess in vivo repeatability, precision errors in mean T2* values, and intraclass correlation coefficients (ICC) were measured from repeat scans. Results showed that CEP T2* values were highest centrally and lowest posteriorly. In the youngest individuals (<50 years), who had mild-to-moderately degenerated Pfirrmann grade II-III discs, low CEP T2* values associated with severer disc degeneration: T1ρ values were 26.7% lower in subjects with low CEP T2* values (P = .025). In older individuals, CEP T2* values did not associate with disc degeneration (P = .39-.62). Precision errors in T2* ranged from 1.7 to 2.6 ms, and reliability was good-to-excellent (ICC = 0.89-0.94). These findings suggest that deficits in CEP composition, as indicated by low T2* values, associate with severer disc degeneration during the mild-to-moderate stages. Measuring CEP T2* values with UTE MRI may clarify the role of CEP composition in patients with mild-to-moderate disc degeneration.
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Multicenter Validation of Association Between Decline in MRI-PDFF and Histologic Response in NASH.
Loomba, R, Neuschwander-Tetri, BA, Sanyal, A, Chalasani, N, Diehl, AM, Terrault, N, Kowdley, K, Dasarathy, S, Kleiner, D, Behling, C, et al
Hepatology (Baltimore, Md.). 2020;(4):1219-1229
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BACKGROUND AND AIMS Emerging data from a single-center study suggests that a 30% relative reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline may be associated with histologic improvement in nonalcoholic steatohepatitis (NASH). There are limited multicenter data comparing an active drug versus placebo on the association between the quantity of liver fat reduction assessed by MRI-PDFF and histologic response in NASH. This study aims to examine the association between 30% relative reduction in MRI-PDFF and histologic response in obeticholic acid (OCA) versus placebo-treated patients in the FLINT (farnesoid X receptor ligand obeticholic acid in NASH trial). APPROACH AND RESULTS This is a secondary analysis of the FLINT trial including 78 patients with MRI-PDFF measured before and after treatment along with paired liver histology assessment. Histologic response was defined as a 2-point improvement in nonalcoholic fatty liver disease activity score without worsening of fibrosis. OCA (25 mg orally once daily) was better than placebo in improving MRI-PDFF by an absolute difference of -3.4% (95% confidence interval [CI], -6.5 to -0.2%, P value = 0.04) and relative difference of -17% (95% CI, -34 to 0%, P value = 0.05). The optimal cutoff point for relative decline in MRI-PDFF for histologic response was 30% (using Youden's index). The rate of histologic response in those who achieved less than 30% decline in MRI-PDFF versus those who achieved a 30% or greater decline in MRI-PDFF (MRI-PDFF responders) relative to baseline was 19% versus 50%, respectively. Compared with MRI-PDFF nonresponders, MRI-PDFF responders demonstrated both a statistically and clinically significant higher odds 4.86 (95% CI, 1.4-12.8, P value < 0.009) of histologic response, including significant improvements in both steatosis and ballooning. CONCLUSION OCA was better than placebo in reducing liver fat. This multicenter trial provides data regarding the association between 30% decline in MRI-PDFF relative to baseline and histologic response in NASH.
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Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI.
Muehe, AM, Siedek, F, Theruvath, AJ, Seekins, J, Spunt, SL, Pribnow, A, Hazard, FK, Liang, T, Daldrup-Link, H
Theranostics. 2020;(8):3612-3621
Abstract
The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on 18F-FDG PET/MRI. Methods: We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with 18F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a 18F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUVmax lesion/SUVmean liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. Results: We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10-6 mm2/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Conclusion: Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.
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Whole-body magnetic resonance imaging as surveillance for subsequent malignancies in preadolescent, adolescent, and young adult survivors of germline retinoblastoma: An update.
Friedman, DN, Hsu, M, Moskowitz, CS, Francis, JH, Lis, E, Fleischut, MH, Oeffinger, KC, Walsh, M, Tonorezos, ES, Sklar, CA, et al
Pediatric blood & cancer. 2020;(7):e28389
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BACKGROUND Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. PROCEDURE WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. RESULTS Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5 years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3 months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). CONCLUSIONS Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.
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Effect of single dose N-acetylcysteine administration on resting state functional connectivity in schizophrenia.
McQueen, G, Lay, A, Lally, J, Gabay, AS, Collier, T, Lythgoe, DJ, Barker, GJ, Stone, JM, McGuire, P, MacCabe, JH, et al
Psychopharmacology. 2020;(2):443-451
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RATIONALE There is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce. OBJECTIVES The aim of this study was to identify the changes in resting-state functional connectivity (rs-FC) that occur following administration of a single dose of NAC in patients with schizophrenia. A secondary aim was to examine whether differences in rs-FC between conditions were mediated by glutamate metabolites in the anterior cingulate cortex (ACC). METHODS In a double-blind, placebo-controlled crossover design, 20 patients with schizophrenia had two MRI scans administered 7 days apart, following oral administration of either 2400 mg NAC or placebo. Resting state functional fMRI (rsfMRI) assessed the effect of NAC on rs-FC within the default mode network (DMN) and the salience network (SN). Proton magnetic resonance spectroscopy was used to measure Glx/Cr (glutamate plus glutamine, in ratio to creatine) levels in the ACC during the same scanning sessions. RESULTS Compared to the placebo condition, the NAC condition was associated with reduced within the DMN and SN, specifically between the medial pre-frontal cortex to mid frontal gyrus, and ACC to frontal pole (all p < 0.04). There were no significant correlations between ACC Glx/Cr and rs-FC in either condition (p > 0.6). CONCLUSIONS These findings provide preliminary evidence that NAC can reduce medial frontal rs-FC in schizophrenia. Future studies assessing the effects of NAC on rs-FC in early psychosis and on repeated administration in relation to efficacy would be of interest.
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Detecting the effects of a standardized meal challenge on small bowel motility with MRI in prepared and unprepared bowel.
de Jonge, CS, Menys, A, van Rijn, KL, Bredenoord, AJ, Nederveen, AJ, Stoker, J
Neurogastroenterology and motility. 2019;(2):e13506
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OBJECTIVE MRI is increasingly used to evaluate small bowel contractility. The objective of this study was to validate a clinically practical stimulation test (300-kcal meal) for small bowel motility. METHODS Thirty-one healthy subjects underwent dynamic MRI to capture global small bowel motility after ±10h fasting, of which 15 underwent bowel preparation consisting of 1 L 2.5% mannitol solution and 16 did not. Each subject underwent (1) a baseline motility scan (2) a food challenge (3) a post-challenge scan, and (4) second post-challenge scan (after ±20 minutes). This protocol was repeated within 2 weeks. Motility was quantified using a validated motility assessment technique. KEY RESULTS Motility in prepared subjects at baseline was significantly higher than motility in unprepared subjects (0.36 AU vs 0.18 AU, P < 0.001). In the prepared group, the food challenge produced an 8% increase in motility (P = 0.33) while in the unprepared subjects a significant increase of 30% was observed (P < 0.001). Responses to food remained insignificant (P = 0.21) and significant (P = 0.003), for the prepared and unprepared subjects, respectively, ±20 minutes post food challenge. These results were confirmed in the repeated scan session. CONCLUSION & INFERENCES A significant response to a 300-kcal meal was measured within 10 minutes in unprepared bowel, supporting the clinical use of this challenge to provoke and assess motility changes. A caloric challenge did not produce an observable increase in motility in mannitol prepared subjects.
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In vivo characterization of enTRinsic™ drug delivery technology capsule after intake in fed state: A cross-validation approach using salivary tracer technique in comparison to MRI.
Sager, M, Grimm, M, Aude, P, Schick, P, Merdivan, S, Hasan, M, Kromrey, ML, Sivert, A, Benameur, H, Koziolek, M, et al
Journal of controlled release : official journal of the Controlled Release Society. 2019;:24-32
Abstract
The instability of various small molecules, vaccines and peptides in the human stomach is a complex challenge for oral drug delivery. Recently, a novel gastro-resistant capsule - the enTRinsic™ Drug Delivery Technology capsule - has been developed. In this work, the salivary tracer technique based on caffeine has been applied to study the in vivo disintegration of enTRinsic™ capsules in 16 healthy volunteers. In addition, magnetic resonance imaging (MRI) was used to visualize GI transit and to verify the disintegration times determined by using the salivary tracer technique. The enTRinsic™ capsules filled with 50mg of caffeine and 5mg of black iron oxide were administered in the fed state, i.e. 30min after a light meal (500kcal). In the first hour after capsule intake, the subjects were placed in supine position in the MRI scanner and scans were performed in short time intervals. After 1h, the subjects could leave the MRI scanner in between the MRI measurements, which were performed every 15min until disintegration of the capsule was confirmed (maximum observation time: 8h). Saliva samples were obtained simultaneously with MR imaging. Caffeine concentrations in saliva were determined by LC/MS-MS. The starting point of capsule disintegration was determined visually by inspection of the MR images as well as by the onset of salivary caffeine concentrations. In 14 out of 16 subjects, the capsule disintegrated in the small intestine. In one subject, the enTRinsic™ capsule was not emptied from the stomach within the observation time. In another subject, disintegration occurred during gastric emptying in the antropyloric region. In this study, we demonstrated that the enTRinsic™ capsules are also gastro resistant when taken under fed state conditions. Furthermore, we demonstrated the feasibility of using low dose caffeine as a salivary tracer for the determination of the disintegration of an enteric formulation.
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Reductions in body weight and insulin resistance are not associated with changes in grey matter volume or cortical thickness during the PREVIEW study.
Drummen, M, Heinecke, A, Dorenbos, E, Vreugdenhil, A, Raben, A, Westerterp-Plantenga, MS, Adam, TC
Journal of the neurological sciences. 2019;:106-111
Abstract
INTRODUCTION The effect of changes in body weight or insulin resistance on grey matter volume and cortical thickness change are unclear. The present observational study assessed effects of an 8-week weight loss period (≥8% of body weight), and a subsequent 22-month weight maintenance period on grey matter volume and cortical thickness. METHODS A total of 24 participants (12f/12 m; age 52.8 ± 10.6 years) with overweight/obesity and pre-diabetes were recruited. T1-weighted magnetic resonance imaging was used to determine grey matter volume and cortical thickness at baseline, after the weight loss period and after a medium to high dietary protein weight maintenance period. RESULTS At baseline, global grey matter volume was inversely associated with HOMA-IR, adjusted for sex and age (r = -0.42; p = .049). During the weight loss period participants decreased their BMI (32.1 ± 3.3 to 28.1 ± 2.8 kg/m2, p < .01), body-fat (41.6 ± 6.4 to 35.0 ± 8.0%, p < .01) and insulin resistance (HOMA-IR: 4.0 ± 2.0 to 1.8 ± 0.9, p < .01). During the 22-month weight maintenance period, these parameters gradually increased again (BMI: 29.3 ± 3.8 kg/m2; body-fat: 37.8 ± 9.3%; HOMA-IR: 2.9 ± 1.4, p < .01). Global grey matter volume and cortical thickness did not change significantly during the weight loss or weight maintenance period. Changes in body weight, body-fat percentage or insulin sensitivity were not associated with changes in global grey matter volume. CONCLUSION In conclusion, we confirmed that global grey brain matter volume was inversely associated with insulin resistance at baseline, yet an intervention yielding a decrease in insulin resistance did not lead to changes in global grey brain matter volume or cortical thickness. TRIAL REGISTRATION The trial is registered with ClinicalTrials.gov, NCT01777893.